Benzothiazolone compound

ABSTRACT

The present invention provides a compound of formula (I) in free form or in pharmaceutically acceptable salt form 
     
       
         
         
             
             
         
       
     
     a method for manufacturing the compound of the invention, and its therapeutic uses. The present invention further provides a combination of pharmacologically active agents and pharmaceutical compositions.

The present invention relates to a benzothiazolone compound, to itspreparation, to its medical use as a beta-2 adrenoceptor agonist and tomedicaments, pharmaceutical compositions and combinations comprising it.

Benzothiazolone compounds which are beta-2-adrenoceptor agonists aredescribed in WO2004/16601 and WO2006/056471. WO2005/110990 alsodescribes benzo-condensed heterocycles as beta-2 agonists.

While beta-2 agonists have long been known for their bronchodilatingproperties, they are also known for their capability to produce skeletalmuscle hypertrophy.

Numerous studies have focused on therapeutic applications of theanabolic properties of beta-2 agonists for ameliorating muscle wastingand improving muscle function. However, this class of compounds has alsobeen associated with undesirable side-effects, including increased riskof adverse cardiovascular-related events. Thus, the use of beta-2agonists in muscle wasting diseases has hitherto been limited by cardiachypertrophy and potentially deleterious effects on cardiovascularfunction.

There is a need to provide new beta-2 agonists that are good drugcandidates. In particular, a new beta-2 agonist should bind potently tothe beta-2 adrenoceptor whilst showing little affinity for otherreceptors, such as e.g. the beta-1 adrenoceptor, the alpha-1Aadrenoceptor, or the 5HT_(2C) receptor, and show functional activity asan agonist. It should be metabolically stable and possess favourablepharmacokinetic properties. It should be non-toxic and demonstrate fewside-effects, in particular fewer cardiac side-effects than knownmarketed beta-2 agonists, such as e.g. formoterol. Furthermore, theideal drug candidate will exist in a physical form that is stable,non-hygroscopic and easily formulated.

The compound of the invention is a selective beta-2 agonist. Inparticular, it shows an increased affinity for the beta-2 adrenoceptorwhich is greater than its affinity for the beta-1 adrenoceptor or thealpha-1A adrenoceptor, compared to known beta-2 agonists such asformoterol. Surprisingly, it also shows a lower affinity for theserotonin receptor (5HT_(2C)) and lower functional potency in 5HT_(2C)expressing cells than its racemate or its corresponding enantiomer,indicating that it does not affect locomotor activity and food intakewhich may cause body weight reduction, potentially counteracting beta-2agonist-induced skeletal muscle hypertrophy. The negative effects of5HT₂, receptor agonists on energy intake and body weight are describedby J. Halford and J. Harrold in Handb Exp Pharmacol. 2012; (209) 349-56.

The compound of the present invention is therefore potentially useful inthe treatment of a wide range of disorders, particularly in thetreatment or prevention of muscle-wasting diseases such as musculardystrophy, disuse-related atrophy, cachexia or sarcopenia.

The treatment of cachexia is also a contemplated use. All forms ofcachexia are potentially treatable with the compounds of the presentinvention, including cancer cachexia for example.

In a first aspect of the invention, there is therefore provided acompound of formula (I) in free form or in pharmaceutically acceptablesalt form which is

The compound of the invention is(R)-7-(2-(1-(4-butoxyphenyl)-2-methylpropan-2-ylamino)-1-hydroxyethyl)-5-hydroxybenzo[d]thiazol-2(3H)-one.

The following are embodiments of the invention:

EMBODIMENT 1

A compound according to the first aspect of the invention.

EMBODIMENT 2

A compound according to embodiment 1 which is(R)-7-(2-(1-(4-butoxyphenyl)-2-methylpropan-2-ylamino)-1-hydroxyethyl)-5-hydroxybenzo[d]thiazol-2(3H)-onein free form.

EMBODIMENT 3

A compound according embodiment 1 which is(R)-7-(2-(1-(4-butoxyphenyl)-2-methylpropan-2-ylamino)-1-hydroxyethyl)-5-hydroxybenzo[d]thiazol-2(3H)-onein acetate salt form.

EMBODIMENT 4

A compound according to embodiment 1 which is(R)-7-(2-(1-(4-butoxyphenyl)-2-methylpropan-2-ylamino)-1-hydroxyethyl)-5-hydroxybenzo[d]thiazol-2(3H)-onein glycolate salt form.

EMBODIMENT 5

A pharmaceutical composition comprising a therapeutically effectiveamount of a compound according to any one of embodiments 1 to 4 and oneor more pharmaceutically acceptable carriers.

EMBODIMENT 6

A pharmaceutical composition according to embodiment 5 wherein one ofthe pharmaceutically acceptable carriers is benzyl alcohol.

EMBODIMENT 7

A combination comprising a therapeutically effective amount of acompound according to any one of embodiments 1 to 4 and one or moretherapeutically active co-agents.

EMBODIMENT 8

A method of treatment or prevention of muscular dystrophy,disuse-related atrophy, cachexia or sarcopenia comprising administeringa therapeutically effective amount of a compound according to any one ofembodiments 1 to 4 to a subject in need thereof.

EMBODIMENT 9

A method according to embodiment 8, wherein the compound is administeredby subcutaneous infusion or injection.

EMBODIMENT 10

A compound according to according to any one of embodiments 1 to 4 foruse as a medicament.

EMBODIMENT 11

A compound according to any one of embodiments 1 to 4 for use in thetreatment or prevention of muscular dystrophy, disuse-related atrophy,cachexia or sarcopenia.

EMBODIMENT 12

Use of a compound according to any one of embodiments 1 to 4 in themanufacture of a medicament for the treatment or prevention of musculardystrophy, disuse-related atrophy, cachexia or sarcopenia.

EMBODIMENT 13

A process for the manufacture of a compound of formula (I) in free formor in pharmaceutically acceptable salt form which includes the steps of:

-   -   a) the reaction of a compound of formula (IIa) in free form or        in pharmaceutically acceptable salt form

-   -    in which R_(a) and R_(b) are protecting groups with        2-(4-butoxy-phenyl)-1,1-dimethyl-ethylamine;    -   b) the cleavage of protecting groups optionally present;    -   c) the recovery of the so obtainable compound of formula (I) in        free form or in pharmaceutically acceptable salt form.

EMBODIMENT 14

A process for the manufacture of a compound of formula (I) in free formor in pharmaceutically acceptable salt form according to embodiment 13in which compound (IIa) is obtained by the reaction of a compound offormula (IIIa) in free form or in pharmaceutically acceptable salt form

in which in which R_(a) and R_(b) are protecting groups and LG is aleaving group with a base and optionally a phase transfer catalyst.

EMBODIMENT 15

A process according to embodiment 14, wherein the base is potassiumcarbonate.

EMBODIMENT 16

A process according to embodiment 14, wherein the base is sodiumhydroxide.

EMBODIMENT 17

A process according to any of embodiments 14 to 16, wherein the phasetransfer catalyst is tetra-butylammonium iodide.

EMBODIMENT 18

A process for the manufacture of a compound of formula (I) in free formor in pharmaceutically acceptable salt form according to embodiments 14to 17 in which compound (IIIa) is obtained by the stereoselectivereduction of a compound of formula (IVa-2) in free form or inpharmaceutically acceptable salt form

in which R_(a) and R_(b) are protecting groups and LG is a leavinggroup.

EMBODIMENT 19

A process according to embodiment 18 wherein the stereoselectivereduction is carried out with[N-[(1S,2S)-2-(Amino-κN)-1,2-diphenylethyl]-4-methylbenzenesulfonamidato-κN]chloro[(1,2,3,4,5,6-q)-1-methyl-4-(1-methylethyl)benzene]-ruthenium(RuCl(p-cymene)[(S,S)-Ts-DPEN]).

EMBODIMENT 20

A process according to embodiment 18 or 19 wherein LG is chloro.

EMBODIMENT 21

A process according to embodiment 20 in which compound (IVa′-2) in freeform or in pharmaceutically acceptable salt form

is obtained by the reaction of a compound of formula (Va) in free formor in pharmaceutically acceptable salt form

in which R_(a) and R_(b) are protecting groups and Hal is a halogen with2-chloro-N-methoxy-N-methyl-acetamide in the presence of a strong base.

EMBODIMENT 22

A process according to embodiment 21, wherein the strong base istert-butyllithium.

EMBODIMENT 23

A process for the manufacture of a compound of formula (I) in free formor in pharmaceutically acceptable salt form which includes the steps of:

-   -   a) the reaction of a compound of formula (IIIa) in free form or        in pharmaceutically acceptable salt form

-   -    in which R_(a) and R_(b) are protecting groups and LG is a        leaving group with 2-(4-butoxy-phenyl)-1,1-dimethyl-ethylamine;    -   b) the cleavage of any protecting groups still present;    -   c) the recovery of the so obtainable compound of formula (I) in        free form or in pharmaceutically acceptable salt form.

EMBODIMENT 24

A process according to embodiment 23, wherein LG is chloro orp-toluenesulfonyl.

EMBODIMENT 25

A process according to any of embodiments 13 to 24 wherein R_(a) istert-butyl.

EMBODIMENT 26

A process according to any of embodiments 13 to 25, wherein R_(b) isisopropyl.

EMBODIMENT 27

A compound of formula (Ia) in free form or in pharmaceuticallyacceptable salt form

in which R_(a) and R_(b) are protecting groups.

EMBODIMENT 28

A compound of formula (IIa) in free form or pharmaceutically acceptablesalt form

in which R_(a) and R_(b) are protecting groups.

EMBODIMENT 29

A compound of formula (IIIa-2) in free form or pharmaceuticallyacceptable salt form

in which R_(a) and R_(b) are protecting groups.

EMBODIMENT 30

A compound of formula (IVa-2) in free form or pharmaceuticallyacceptable salt form

in which R_(a) and R_(b) are protecting groups and LG is a leavinggroup.

EMBODIMENT 31

A compound according to embodiment 30, wherein LG is chloro.

EMBODIMENT 32

A compound according to any of embodiments 27 to 31, wherein R_(a) istert-butyl.

EMBODIMENT 33

A compound according to any of embodiments 27 to 32, wherein R_(b) isisopropyl.

BRIEF DESCRIPTION OF FIGURES

FIG. 1 shows the skeletal muscle mass and heart mass increase in ratsinjected with formoterol vs compound A (compound of theinvention)—(values are expressed as means±SEM (n=5-6); pool of skeletalmuscles (gastrocnemius-soleus-tibialis) normalized by initial bodyweight; heart weight normalized by brain weight.

FIG. 2 a shows the increase of beating rate in isolated rabbit sinθ-atrial nodes when using formoterol vs compound A (compound of theinvention).

FIG. 2 b shows the increase of pacemaker activity in isolated rabbithearts when using formoterol vs compound A (compound of the invention).

FIGS. 3 a and 3 b show the heart rate change in rats upon a s.c. bolusinjection of Compound A (compound of the invention) or formoterolrespectively.

FIG. 3 c compares the average heart rate change in rats whenadministering formoterol vs compound A (compound of the invention).

FIGS. 4 a and 4 b show the heart rate change in rhesus monkeys upon as.c. bolus injection of Compound A (compound of the invention) orformoterol respectively.

FIG. 5 shows the X-ray powder diffraction pattern of crystalline freebase Compound A (compound of the invention).

FIG. 6 shows the X-ray powder diffraction pattern of the crystallineacetate salt of Compound A (compound of the invention).

FIG. 7 shows the X-ray powder diffraction pattern of the crystallineglycolate salt of Compound A (compound of the invention).

Unless specified otherwise, the term “compound of the presentinvention”, “compound of the invention” or “compound A” refers to thecompound of formula (I), salts of the compound, hydrates or solvates ofthe compound or salts, as well as tautomers and isotopically labeledcompounds (including deuterium substitutions). The compound of thepresent invention further comprises polymorphs of the compound offormula (I) and salts thereof.

As used herein, the term “halogen” or “halo” refers to fluoro, chloro,bromo, and iodo.

As used herein, the absolute stereochemistry is specified according tothe Cahn-Ingold-Prelog R-S system. When a compound is a pure enantiomerthe stereochemistry at each chiral carbon may be specified by either Ror S. Resolved compounds whose absolute configuration is unknown can bedesignated (+) or (−) depending on the direction (dextro- orlevorotatory) which they rotate plane polarized light at the wavelengthof the sodium D line. Any asymmetric atom (e.g., carbon or the like) ofa compound can be present in racemic or enantiomerically enriched, forexample the (R)-, (S)- or (R,S)-configuration. The racemic 50:50 mixtureof stereoisomers is designated as (R,S) and enantiomerically enrichedforms by the enantiomeric excess of (R) to (S) respectively or (S) to(R) forms. The enantiomeric excess is represented usually by theequation ee=((m1−m2)/(m1+m2))*100% where m1 and m2 represent the mass ofthe respective enantiomeric forms R and S.

The compound of the present invention contains one asymmetric centrewhich is defined in terms of absolute stereochemistry as (R). Itscorresponding enantiomer is defined as (S) which is the less activeform.

In certain embodiments of the invention, the asymmetric atom has atleast 95, 98 or 99% enantiomeric excess in the (R)-configuration.

Thus in one embodiment of the invention, there is provided(R)-7-(2-(1-(4-butoxyphenyl)-2-methylpropan-2-ylamino)-1-hydroxyethyl)-5-hydroxybenzo[d]thiazol-2(3H)-one,or a pharmaceutically acceptable salt thereof (for example an acetate orglycolate salt thereof), in at least 95% enantiomeric excess.

In another embodiment of the invention, there is provided(R)-7-(2-(1-(4-butoxyphenyl)-2-methylpropan-2-ylamino)-1-hydroxyethyl)-5-hydroxybenzo[d]thiazol-2(3H)-one,or a pharmaceutically acceptable salt thereof (for example an acetate orglycolate salt thereof), in at least 98% enantiomeric excess.

In yet another embodiment of the invention, there is provided(R)-7-(2-(1-(4-butoxyphenyl)-2-methylpropan-2-ylamino)-1-hydroxyethyl)-5-hydroxybenzo[d]thiazol-2(3H)-one,or a pharmaceutically acceptable salt thereof (for example an acetate orglycolate salt thereof), in at least 99% enantiomeric excess.

In one embodiment of the invention, there is provided a pharmaceuticalcomposition comprising a therapeutically effective amount of(R)-7-(2-(1-(4-butoxyphenyl)-2-methylpropan-2-ylamino)-1-hydroxyethyl)-5-hydroxybenzo[d]thiazol-2(3H)-one,or a pharmaceutically acceptable salt thereof (for example an acetate orglycolate salt thereof), and one or more pharmaceutically acceptablecarriers wherein the(R)-7-(2-(1-(4-butoxyphenyl)-2-methylpropan-2-ylamino)-1-hydroxyethyl)-5-hydroxybenzo[d]thiazol-2(3H)-one,or pharmaceutically acceptable salt thereof, is present in at least 95%enantiomeric excess.

In another embodiment of the invention, there is provided apharmaceutical composition comprising a therapeutically effective amountof(R)-7-(2-(1-(4-butoxyphenyl)-2-methylpropan-2-ylamino)-1-hydroxyethyl)-5-hydroxybenzo[d]thiazol-2(3H)-one,or a pharmaceutically acceptable salt thereof (for example an acetate orglycolate salt thereof), and one or more pharmaceutically acceptablecarriers wherein the(R)-7-(2-(1-(4-butoxyphenyl)-2-methylpropan-2-ylamino)-1-hydroxyethyl)-5-hydroxybenzo[d]thiazol-2(3H)-one,or pharmaceutically acceptable salt thereof, is present in at least 98%enantiomeric excess.

In yet another embodiment of the invention, there is provided apharmaceutical composition comprising a therapeutically effective amountof(R)-7-(2-(1-(4-butoxyphenyl)-2-methylpropan-2-ylamino)-1-hydroxyethyl)-5-hydroxybenzo[d]thiazol-2(3H)-one,or a pharmaceutically acceptable salt thereof (for example an acetate orglycolate salt thereof), and one or more pharmaceutically acceptablecarriers wherein the(R)-7-(2-(1-(4-butoxyphenyl)-2-methylpropan-2-ylamino)-1-hydroxyethyl)-5-hydroxybenzo[d]thiazol-2(3H)-one,or pharmaceutically acceptable salt thereof, is present in at least 99%enantiomeric excess.

The compound of the present invention contains one asymmetric centrewhich is defined in terms of absolute stereochemistry as (R). Itscorresponding enantiomer is defined as (S).

Depending on the choice of the starting materials and procedures for thechemical synthesis, compounds can be present in the form of one of thepossible isomers or as mixtures thereof, for example as pure opticalisomers, or as isomer mixtures, such as racemates. Optically active (R)-and (S)-isomers may be prepared using chiral synthons or chiralreagents, or resolved using conventional techniques. All tautomericforms of the compound of the present invention are intended to beincluded.

Accordingly, as used herein the compound of the present invention can bein the form of tautomers or mixtures thereof.

Any resulting racemates of final products or synthesis intermediates canbe resolved into the optical antipodes by known methods, e.g., byseparation of the diastereomeric salts thereof, obtained with anoptically active acid or base, and liberating the optically activeacidic or basic compound. In particular, a basic moiety may thus beemployed to resolve the compound of the present invention into itsoptical antipodes, e.g., by fractional crystallization of a salt formedwith an optically active acid, e.g., tartaric acid, dibenzoyl tartaricacid, diacetyl tartaric acid, di-O,O′-p-toluoyl tartaric acid, mandelicacid, malic acid or camphor-10-sulfonic acid. Racemic orenantiomerically enriched products can also be resolved by chiralchromatography, e.g., high pressure liquid chromatography (HPLC) using achiral adsorbent.

As used herein, the terms “salt” or “salts” refers to an acid additionor base addition salt of the compound of the invention. “Salts” includein particular “pharmaceutically acceptable salts”. The term“pharmaceutically acceptable salts” refers to salts that retain thebiological effectiveness and properties of the compound of thisinvention and, which typically are not biologically or otherwiseundesirable. The compound of formula I of the present invention iscapable of forming a characteristic salt with a defined acid by virtueof the presence of a basic amino group in the side chain. It is alsocapable to form characteristic salts with defined bases by virtue of thepresence of two acidic groups (phenol; thiazolone ring) in theheterocylic moiety.

Pharmaceutically acceptable acid addition salts may be formed withinorganic acids and organic acids, e.g., acetate, aspartate, benzoate,besylate, bromide/hydrobromide, bicarbonate/carbonate,bisulfate/sulfate, camphorsulfonate, chloride/hydrochloride,chlortheophyllonate, citrate, ethandisulfonate, fumarate, gluceptate,gluconate, glucuronate, glycolic, hippurate, hydroiodide/iodide,isethionate, lactate, lactobionate, laurylsulfate, malate, maleate,malonate, mandelate, mesylate, methylsulphate, naphthoate, napsylate,nicotinate, nitrate, octadecanoate, oleate, oxalate, palmitate, pamoate,phosphate/hydrogen phosphate/dihydrogen phosphate, polygalacturonate,propionate, stearate, succinate, sulfosalicylate, tartrate, tosylate andtrifluoroacetate salts.

In one embodiment of the invention, there is provided(R)-7-(2-(1-(4-butoxyphenyl)-2-methylpropan-2-ylamino)-1-hydroxyethyl)-5-hydroxybenzo[d]thiazol-2(3H)-onein acetate, benzoate, camphorate, fumarate, glycolate, lactate,malonate, mesylate, succinate, sulfate, tartrate or xinafoate salt form.

In one particular embodiment of the invention, there is provided(R)-7-(2-(1-(4-butoxyphenyl)-2-methylpropan-2-ylamino)-1-hydroxyethyl)-5-hydroxybenzo[d]thiazol-2(3H)-onein acetate salt form.

In another particular embodiment of the invention, there is provided(R)-7-(2-(1-(4-butoxyphenyl)-2-methylpropan-2-ylamino)-1-hydroxyethyl)-5-hydroxybenzo[d]thiazol-2(3H)-onein glycolate salt form.

Inorganic acids from which salts may be derived include, for example,hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid,phosphoric acid, and the like.

Organic acids from which salts may be derived include, for example,acetic acid, propionic acid, glycolic acid, oxalic acid, maleic acid,malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid,benzoic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid,toluenesulfonic acid, sulfosalicylic acid, and the like.

Pharmaceutically acceptable base addition salts may be formed withinorganic and organic bases.

Inorganic bases from which salts may be derived include, for example,ammonium salts and metals from columns I to XII of the periodic table.In certain embodiments, the salts are derived from sodium, potassium,ammonium, calcium, magnesium and iron; particularly suitable saltsinclude ammonium, potassium, sodium, calcium and magnesium salts.

Organic bases from which salts may be derived include, for example,primary, secondary, and tertiary amines, substituted amines includingnaturally occurring substituted amines, cyclic amines, basic ionexchange resins, and the like. Certain organic amines includeisopropylamine, benzathine, cholinate, diethanolamine, diethylamine,lysine, meglumine, piperazine and tromethamine.

The pharmaceutically acceptable salts of the present invention can besynthesized from a basic or acidic moiety, by conventional chemicalmethods. Generally, such salts can be prepared by reacting free acidforms of the compound with a stoichiometric amount of the appropriatebase (such as Na, Ca, Mg, or K hydroxide, carbonate, bicarbonate or thelike), or by reacting free base forms of the compounds with astoichiometric amount of the appropriate acid. Such reactions aretypically carried out in water or in an organic solvent, or in a mixtureof the two. Generally, use of non-aqueous media like ether, ethylacetate, ethanol, isopropanol, or acetonitrile is desirable, wherepracticable. Lists of additional suitable salts can be found, e.g., in“Remington's Pharmaceutical Sciences”, 20th ed., Mack PublishingCompany, Easton, Pa., (1985); and in “Handbook of Pharmaceutical Salts:Properties, Selection, and Use” by Stahl and Wermuth (Wiley-VCH,Weinheim, Germany, 2^(nd) revised edition, 2011).

Furthermore, the compound of the present invention, including its salts,may also be obtained in the form of its hydrates, or include othersolvents used for its crystallization. The compound of the presentinvention may inherently or by design form solvates withpharmaceutically acceptable solvents (including water); therefore, it isintended that the invention embrace both solvated and unsolvated forms.The term “solvate” refers to a molecular complex of the compound of thepresent invention (including pharmaceutically acceptable salts thereof)with one or more solvent molecules. Such solvent molecules are thosecommonly used in the pharmaceutical art, which are known to be innocuousto the recipient, e.g., water, ethanol, and the like. The term “hydrate”refers to the complex where the solvent molecule is water.

The compound of the present invention, including salts, hydrates andsolvates thereof, may inherently or by design form polymorphs.

In one embodiment of the invention, there is provided(R)-7-(2-(1-(4-butoxyphenyl)-2-methylpropan-2-ylamino)-1-hydroxyethyl)-5-hydroxybenzo[d]thiazol-2(3H)-onein crystalline form.

In another embodiment of the invention, there is provided(R)-7-(2-(1-(4-butoxyphenyl)-2-methylpropan-2-ylamino)-1-hydroxyethyl)-5-hydroxybenzo[d]thiazol-2(3H)-oneacetate salt in crystalline form.

In yet another embodiment of the invention, there is provided(R)-7-(2-(1-(4-butoxyphenyl)-2-methylpropan-2-ylamino)-1-hydroxyethyl)-5-hydroxybenzo[d]thiazol-2(3H)-oneglycolate salt in crystalline form.

In one embodiment of the invention, there is provided crystalline(R)-7-(2-(1-(4-butoxyphenyl)-2-methylpropan-2-ylamino)-1-hydroxyethyl)-5-hydroxybenzo[d]thiazol-2(3H)-onein substantially pure form.

In another embodiment of the invention, there is provided crystalline(R)-7-(2-(1-(4-butoxyphenyl)-2-methylpropan-2-ylamino)-1-hydroxyethyl)-5-hydroxybenzo[d]thiazol-2(3H)-oneacetate salt in substantially pure form.

In yet another embodiment of the invention, there is providedcrystalline(R)-7-(2-(1-(4-butoxyphenyl)-2-methylpropan-2-ylamino)-1-hydroxyethyl)-5-hydroxybenzo[d]thiazol-2(3H)-oneglycolate salt in substantially pure form.

As used herein, “substantially pure,” when used in reference tocrystalline(R)-7-(2-(1-(4-butoxyphenyl)-2-methylpropan-2-ylamino)-1-hydroxyethyl)-5-hydroxybenzo[d]thiazol-2(3H)-one,or its pharmaceutically acceptable salt, means having a purity greaterthan 90 weight %, including greater than 90, 91, 92, 93, 94, 95, 96, 97,98, and 99 weight %, and also including equal to about 100 weight % of(R)-7-(2-(1-(4-butoxyphenyl)-2-methylpropan-2-ylamino)-1-hydroxyethyl)-5-hydroxybenzo[d]thiazol-2(3H)-one,based on the weight of the compound, or its pharmaceutically acceptablesalt.

The presence of reaction impurities and/or processing impurities may bedetermined by analytical techniques known in the art, such as, forexample, chromatography, nuclear magnetic resonance spectroscopy, massspectrometry, or infrared spectroscopy.

In a more focused aspect, the invention relates to a crystalline form of(R)-7-(2-(1-(4-butoxyphenyl)-2-methylpropan-2-ylamino)-1-hydroxyethyl)-5-hydroxybenzo[d]thiazol-2(3H)-onewhich has an X-ray powder diffraction pattern with at least one, two orthree peaks having angle of refraction 2 theta (θ) values selected from8.5, 13.3, 13.9, 14.4, 15.2, 17.2, 17.5, 18.1, 21.3 and 22.5° whenmeasured using CuK_(α) radiation, more particularly wherein said valuesare plus or minus 0.2° 2θ.

In one embodiment, the invention relates to a crystalline form of(R)-7-(2-(1-(4-butoxyphenyl)-2-methylpropan-2-ylamino)-1-hydroxyethyl)-5-hydroxybenzo[d]thiazol-2(3H)-onewhich has an X-ray powder diffraction pattern with a peak at an angle ofrefraction 2θ value of 15.2° when measured using CuK_(α) radiation, moreparticularly wherein said value is plus or minus 0.2° 2θ.

In one embodiment, the invention relates to a crystalline form of(R)-7-(2-(1-(4-butoxyphenyl)-2-methylpropan-2-ylamino)-1-hydroxyethyl)-5-hydroxybenzo[d]thiazol-2(3H)-onewhich has an X-ray powder diffraction pattern with a peak at an angle ofrefraction 2θ value of 18.1° when measured using CuK_(α) radiation, moreparticularly wherein said value is plus or minus 0.2° 2θ.

In one embodiment, the invention relates to a crystalline form of(R)-7-(2-(1-(4-butoxyphenyl)-2-methylpropan-2-ylamino)-1-hydroxyethyl)-5-hydroxybenzo[d]thiazol-2(3H)-onewhich has an X-ray powder diffraction pattern with a peak at an angle ofrefraction 2θ value of 22.5° when measured using CuK_(α) radiation, moreparticularly wherein said value is plus or minus 0.2° 2θ.

In one embodiment, the invention relates to a crystalline form of(R)-7-(2-(1-(4-butoxyphenyl)-2-methylpropan-2-ylamino)-1-hydroxyethyl)-5-hydroxybenzo[d]thiazol-2(3H)-onewhich has an X-ray powder diffraction pattern substantially the same asthe X-ray powder diffraction pattern shown in FIG. 5 when measured usingCuK_(α) radiation. For details see Example 5.

In another aspect, the invention relates to a crystalline form of theacetate salt of(R)-7-(2-(1-(4-butoxyphenyl)-2-methylpropan-2-ylamino)-1-hydroxyethyl)-5-hydroxybenzo[d]thiazol-2(3H)-onewhich has an X-ray powder diffraction pattern with at least one, two orthree peaks having angle of refraction 2 theta (θ) values selected from8.8, 11.5, 16.4, 17.6, 18.2, 19.6, 20.1, 20.8, and 21.1° when measuredusing CuK_(α) radiation, more particularly wherein said values are plusor minus 0.2° 2θ.

In one embodiment, the invention relates to a crystalline form of theacetate salt of(R)-7-(2-(1-(4-butoxyphenyl)-2-methylpropan-2-ylamino)-1-hydroxyethyl)-5-hydroxybenzo[d]thiazol-2(3H)-onewhich has an X-ray powder diffraction pattern with a peak at an angle ofrefraction 2θ value of 8.8° when measured using CuK_(α) radiation, moreparticularly wherein said value is plus or minus 0.2° 2θ.

In one embodiment, the invention relates to a crystalline form of theacetate salt of(R)-7-(2-(1-(4-butoxyphenyl)-2-methylpropan-2-ylamino)-1-hydroxyethyl)-5-hydroxybenzo[d]thiazol-2(3H)-onewhich has an X-ray powder diffraction pattern with a peak at an angle ofrefraction 2θ value of 16.4° when measured using CuK_(α) radiation, moreparticularly wherein said value is plus or minus 0.2° 2θ.

In one embodiment, the invention relates to a crystalline form of theacetate salt of(R)-7-(2-(1-(4-butoxyphenyl)-2-methylpropan-2-ylamino)-1-hydroxyethyl)-5-hydroxybenzo[d]thiazol-2(3H)-onewhich has an X-ray powder diffraction pattern with a peak at an angle ofrefraction 2θ value of 20.8° when measured using CuK_(α) radiation, moreparticularly wherein said value is plus or minus 0.2° 2θ.

In one embodiment, the invention relates to a crystalline form of theacetate salt of(R)-7-(2-(1-(4-butoxyphenyl)-2-methylpropan-2-ylamino)-1-hydroxyethyl)-5-hydroxybenzo[d]thiazol-2(3H)-onewhich has an X-ray powder diffraction pattern substantially the same asthe X-ray powder diffraction pattern shown in FIG. 6 when measured usingCuK_(α) radiation. For details see Example 6.

In yet another aspect, the invention relates to a crystalline form ofthe glycolate salt of(R)-7-(2-(1-(4-butoxyphenyl)-2-methylpropan-2-ylamino)-1-hydroxyethyl)-5-hydroxybenzo[d]thiazol-2(3H)-onewhich has an X-ray powder diffraction pattern with at least one, two orthree peaks having angle of refraction 2 theta (θ) values selected from8.7, 11.6, 16.1, 18.0, 19.8, 20.7, and 21.1° when measured using CuK_(α)radiation, more particularly wherein said values are plus or minus 0.2°2θ.

In one embodiment, the invention relates to a crystalline form of theglycolate salt of(R)-7-(2-(1-(4-butoxyphenyl)-2-methylpropan-2-ylamino)-1-hydroxyethyl)-5-hydroxybenzo[d]thiazol-2(3H)-onewhich has an X-ray powder diffraction pattern with a peak at an angle ofrefraction 2θ value of 18.0° when measured using CuK_(α) radiation, moreparticularly wherein said value is plus or minus 0.2° 2θ.

In one embodiment, the invention relates to a crystalline form of theglycolate salt of(R)-7-(2-(1-(4-butoxyphenyl)-2-methylpropan-2-ylamino)-1-hydroxyethyl)-5-hydroxybenzo[d]thiazol-2(3H)-onewhich has an X-ray powder diffraction pattern with a peak at an angle ofrefraction 2θ value of 19.8° when measured using CuK_(α) radiation, moreparticularly wherein said value is plus or minus 0.2° 2θ.

In one embodiment, the invention relates to a crystalline form of theglycolate salt of(R)-7-(2-(1-(4-butoxyphenyl)-2-methylpropan-2-ylamino)-1-hydroxyethyl)-5-hydroxybenzo[d]thiazol-2(3H)-onewhich has an X-ray powder diffraction pattern with a peak at an angle ofrefraction 2θ value of 20.7° when measured using CuK_(α) radiation, moreparticularly wherein said value is plus or minus 0.2° 2θ.

In one embodiment, the invention relates to a crystalline form of theglycolate salt of(R)-7-(2-(1-(4-butoxyphenyl)-2-methylpropan-2-ylamino)-1-hydroxyethyl)-5-hydroxybenzo[d]thiazol-2(3H)-onewhich has an X-ray powder diffraction pattern substantially the same asthe X-ray powder diffraction pattern shown in FIG. 7 when measured usingCuK_(α) radiation. For details see Example 7.

The term “substantially the same” with reference to X-ray diffractionpeak positions means that typical peak position and intensityvariability are taken into account. For example, one skilled in the artwill appreciate that the peak positions (20) will show someinter-apparatus variability, typically as much as 0.2°. Further, oneskilled in the art will appreciate that relative peak intensities willshow inter-apparatus variability as well as variability due to degree ofcrystallinity, preferred orientation, prepared sample surface, and otherfactors known to those skilled in the art, and should be taken asqualitative measures only.

One of ordinary skill in the art will also appreciate that an X-raydiffraction pattern may be obtained with a measurement error that isdependent upon the measurement conditions employed. In particular, it isgenerally known that intensities in an X-ray diffraction pattern mayfluctuate depending upon measurement conditions employed. It should befurther understood that relative intensities may also vary dependingupon experimental conditions and, accordingly, the exact order ofintensity should not be taken into account. Additionally, a measurementerror of diffraction angle for a conventional X-ray diffraction patternis typically about 5% or less, and such degree of measurement errorshould be taken into account as pertaining to the aforementioneddiffraction angles. Consequently, it is to be understood that thecrystal forms of the instant invention is not limited to the crystalform that provides an X-ray diffraction pattern completely identical tothe X-ray diffraction pattern depicted in the accompanying FIGS. 5, 6and 7 disclosed herein. Any crystal forms that provide X-ray diffractionpatterns substantially identical to those disclosed in the accompanyingFIGS. 5, 6 and 7 fall within the scope of the present invention. Theability to ascertain substantial identities of X-ray diffractionpatterns is within the purview of one of ordinary skill in the art.

Pharmaceutically acceptable solvates in accordance with the inventioninclude those wherein the solvent of crystallization may be isotopicallysubstituted, e.g. D₂O, d₆-acetone, d₆-DMSO.

The formula given herein is also intended to represent unlabeled formsas well as isotopically labeled forms of the compound. An isotopicallylabeled compound of the invention has a structure depicted by theformula given herein except that one or more atoms are replaced by anatom having a selected atomic mass or mass number. Examples of isotopesthat can be incorporated into the compound of the invention includeisotopes of hydrogen, carbon, nitrogen, oxygen, phosphorous, fluorine,and chlorine, such as ²H, ³H, ¹¹C, ¹³C, ¹⁴C, ¹⁵N, ¹⁸F ³¹P, ³²F, ³⁵S,³⁶Cl, ¹²⁵I respectively. The invention includes various isotopicallylabeled compounds as defined herein, for example those into whichradioactive isotopes, such as ³H and ¹⁴C, or those into whichnon-radioactive isotopes, such as ²H and ¹³C are present. Suchisotopically labelled compounds are useful in metabolic studies (with¹⁴C), reaction kinetic studies (with, for example ²H or ³H), detectionor imaging techniques, such as positron emission tomography (PET) orsingle-photon emission computed tomography (SPECT) including drug orsubstrate tissue distribution assays, or in radioactive treatment ofpatients. In particular, an ¹⁸F or labeled compound may be particularlydesirable for PET or SPECT studies. An isotopically-labeled compound offormula (I) can generally be prepared by conventional techniques knownto those skilled in the art or by processes analogous to those describedin the accompanying Examples using an appropriate isotopically-labeledreagent in place of the non-labeled reagent previously employed.

Further, substitution with heavier isotopes, particularly deuterium(i.e., ²H or D) may afford certain therapeutic advantages resulting fromgreater metabolic stability, for example increased in vivo half-life orreduced dosage requirements or an improvement in therapeutic index. Itis understood that deuterium in this context is regarded as asubstituent of a compound of the formula (I). The concentration of sucha heavier isotope, specifically deuterium, may be defined by theisotopic enrichment factor. The term “isotopic enrichment factor” asused herein means the ratio between the isotopic abundance and thenatural abundance of a specified isotope. If a substituent in thecompound of this invention is denoted deuterium, such compound has anisotopic enrichment factor for each designated deuterium atom of atleast 3500 (52.5% deuterium incorporation at each designated deuteriumatom), at least 4000 (60% deuterium incorporation), at least 4500 (67.5%deuterium incorporation), at least 5000 (75% deuterium incorporation),at least 5500 (82.5% deuterium incorporation), at least 6000 (90%deuterium incorporation), at least 6333.3 (95% deuterium incorporation),at least 6466.7 (97% deuterium incorporation), at least 6600 (99%deuterium incorporation), or at least 6633.3 (99.5% deuteriumincorporation).

The compound of the invention may be capable of forming co-crystals withsuitable co-crystal formers. These co-crystals may be prepared from acompound of formula (I) by known co-crystal forming procedures. Suchprocedures include grinding, heating, co-subliming, co-melting, orcontacting in solution a compound of formula (I) with the co-crystalformer under crystallization conditions and isolating co-crystalsthereby formed. Suitable co-crystal formers include those described inWO 2004/078163. Hence the invention further provides co-crystalscomprising a compound of formula (I).

As used herein, the term “pharmaceutically acceptable carrier” includesany and all solvents, dispersion media, coatings, surfactants,antioxidants, preservatives (e.g., antibacterial agents, antifungalagents), isotonic agents, absorption delaying agents, salts,preservatives, drug stabilizers, binders, excipients, disintegrationagents, lubricants, sweetening agents, flavoring agents, dyes, and thelike and combinations thereof, as would be known to those skilled in theart (see, for example, Remington's Pharmaceutical Sciences, 18th Ed.Mack Printing Company, 1990, pp. 1289-1329). Except insofar as anyconventional carrier is incompatible with the active ingredient, its usein the therapeutic or pharmaceutical compositions is contemplated.

The term “a therapeutically effective amount” of the compound of thepresent invention refers to an amount of the compound of the presentinvention that will elicit the biological or medical response of asubject, for example, reduction or inhibition of an enzyme or a proteinactivity, or ameliorate symptoms, alleviate conditions, slow or delaydisease progression, or prevent a disease, etc. In one non-limitingembodiment, the term “a therapeutically effective amount” refers to theamount of the compound of the present invention that, when administeredto a subject, is effective to (1) at least partially alleviating,inhibiting, preventing and/or ameliorating a condition, or a disorder ora disease associated with beta-2-adrenoceptor activity; or (2)increasing or promoting the activity of beta-2-adrenoceptor.

In another non-limiting embodiment, the term “a therapeuticallyeffective amount” refers to the amount of the compound of the presentinvention that, when administered to a cell, or a tissue, or anon-cellular biological material, or a medium, is effective to at leastpartially increase or promote the activity of beta-2-adrenoceptor. Themeaning of the term “a therapeutically effective amount” as illustratedin the above embodiment for beta-2-adrenoceptor also applies by the samemeans to any other relevant proteins/peptides/enzymes, such as IGF-1mimetics or ActRIIB/myostatin blockers and the like.

As used herein, the term “subject” refers to an animal. Typically theanimal is a mammal. A subject also refers to for example, primates(e.g., humans, male or female), cows, sheep, goats, horses, dogs, cats,rabbits, rats, mice, fish, birds and the like. In certain embodiments,the subject is a primate. In yet other embodiments, the subject is ahuman.

As used herein, the term “inhibit”, “inhibition” or “inhibiting” refersto the reduction or suppression of a given condition, symptom, ordisorder, or disease, or a significant decrease in the baseline activityof a biological activity or process.

As used herein, the term “treat”, “treating” or “treatment” of anydisease or disorder refers in one embodiment, to ameliorating thedisease or disorder (i.e., slowing or arresting or reducing thedevelopment of the disease or at least one of the clinical symptomsthereof). In another embodiment “treat”, “treating” or “treatment”refers to alleviating or ameliorating at least one physical parameterincluding those which may not be discernible by the patient. In yetanother embodiment, “treat”, “treating” or “treatment” refers tomodulating the disease or disorder, either physically, (e.g.,stabilization of a discernible symptom), physiologically, (e.g.,stabilization of a physical parameter), or both. In yet anotherembodiment, “treat”, “treating” or “treatment” refers to preventing ordelaying the onset or development or progression of the disease ordisorder.

As used herein, a subject is “in need of” a treatment if such subjectwould benefit biologically, medically or in quality of life from suchtreatment.

As used herein, the term “a,” “an,” “the” and similar terms used in thecontext of the present invention (especially in the context of theclaims) are to be construed to cover both the singular and plural unlessotherwise indicated herein or clearly contradicted by the context.

All methods described herein can be performed in any suitable orderunless otherwise indicated herein or otherwise clearly contradicted bycontext. The use of any and all examples, or exemplary language (e.g.“such as”) provided herein is intended merely to better illustrate theinvention and does not pose a limitation on the scope of the inventionotherwise claimed.

The compound of formula (I) can be prepared according to the Schemeprovided infra.

The process steps are described in more details below.

Step 1: A compound of formula (VIa) wherein Hal represents halogen andR_(a) is a protecting group is reacted with a compound of formulaR_(b)OH wherein R_(b) is a protecting group in the presence of asuitable base, e.g. triethylamine, to give a compound of formula (Va)wherein Hal represents halogen and R_(a) and R_(b) are protectinggroups.

Step 2: A compound of formula (Va) is reacted with a suitable strongbase, e.g. tert-butyllithium, in a suitable solvent, e.g.tetrahydrofuran (THF) in the presence of a suitable carbonylating agent,e.g. a suitable amide, to give a compound of formula (IVa) wherein R_(a)and R_(b) are protecting groups and R_(c) is hydrogen or any moietyderived from the carbonylating agent.

Step 3: A compound of formula (IVa) is optionally functionalised priorto stereoselective conversion to give a compound of formula (IIIa)wherein R_(a) and R_(b) are protecting groups and LG is a leaving group.

Step 4: A compound of formula (IIIa) is treated with a suitable base,e.g. sodium bicarbonate, to give a compound of formula (IIa) whereinR_(a) and R_(b) are protecting groups.

Step 5: A compound of formula (IIa) or (IIIa) is reacted with2-(4-butoxy-phenyl)-1,1-dimethyl-ethylamine in a suitable solvent e.g.toluene, optionally in the presence of a suitable base, e.g. potassiumcarbonate, followed by deprotection in the presence of a suitable acid,e.g. hydrochloric acid, to give a compound of formula (I).

In a further aspect, the invention relates to a process for thepreparation of a compound of formula (I), in free from or inpharmaceutically acceptable salt form, comprising

-   -   a) the reaction of a compound of formula (IIa) in free form or        in pharmaceutically acceptable salt form

-   -    in which R_(a) and R_(b) are protecting groups with        2-(4-butoxy-phenyl)-1,1-dimethyl-ethylamine;    -   b) the cleavage of any protecting groups still present;    -   c) the recovery of the so obtainable compound of formula (I) in        free form or in pharmaceutically acceptable salt form.

In a further aspect, the invention relates to a process for themanufacture of a compound of formula (I) in free form or inpharmaceutically acceptable salt form which includes the steps of:

-   -   a) the reaction of a compound of formula (IIIa) in free form or        in pharmaceutically acceptable salt form

-   -   in which R_(a) and R_(b) are protecting groups and LG is a        leaving group with 2-(4-butoxy-phenyl)-1,1-dimethyl-ethylamine;    -   b) the cleavage of any protecting groups still present;    -   c) the recovery of the so obtainable compound of formula (I) in        free form or in pharmaceutically acceptable salt form.

In another aspect, the invention relates to a process for thepreparation of a compound of formula (IIIa), in free from or inpharmaceutically acceptable salt form,

comprising the stereoselective reduction of a compound of formula(IVa-2) in free form or in pharmaceutically acceptable salt form

in which R_(a) and R_(b) are protecting groups and LG is a leaving groupto give a compound of formula (IIIa) in free form or in pharmaceuticallyacceptable salt form.

In the processes of the invention, typical protecting groups includeisopropyl, tert-butyl, tert-butyldimethylsilyl.

In the processes of the invention, typical leaving groups includechloride, p-toluenesulfonyl, bromide, methanesulfonyl, benzenesulfonyl,iodide.

The reactions can be effected according to conventional methods, forexample as described in the Examples. The work-up of the reactionmixtures and the purification of the compounds thus obtainable may becarried out in accordance with known procedures. Acid addition salts maybe produced from the free bases in known manner, and vice-versa.Compound of formula (I) can also be prepared by further conventionalprocesses, for example as described in the Examples, which processes arefurther aspects of the invention.

The starting materials used are known or may be prepared according toconventional procedures starting from known compounds, for example asdescribed in the Examples.

The invention further includes any variant of the present processes, inwhich an intermediate product obtainable at any stage thereof is used asstarting material and the remaining steps are carried out, or in whichthe starting materials are formed in situ under the reaction conditions,or in which the reaction components are used in the form of their saltsor optically pure material.

The compound of the invention and intermediates can also be convertedinto each other according to methods generally known to those skilled inthe art.

In a further aspect, the invention relates to a compound of formula(IIa) in free form or in pharmaceutically acceptable salt form

wherein R_(a) and R_(b) are protecting groups.

R_(a) and R_(b) may be independently selected from the group includingtert-butyl, isopropyl and tert-butyldimethylsilyl.

In a further aspect, the invention relates to a compound of formula(IIIa-2) in free form or in pharmaceutically acceptable salt form

wherein R_(a) and R_(b) are protecting groups.

R_(a) and R_(b) may be independently selected from the group includingtert-butyl, isopropyl and tert-butyldimethylsilyl.

In a further aspect, the invention relates to a compound of formula (Ia)in free form or in pharmaceutically acceptable salt form

wherein R_(a) and R_(b) are protecting groups.

R_(a) and R_(b) may be independently selected from the group includingtert-butyl, isopropyl and tert-butyldimethylsilyl.

In another aspect, the present invention provides a pharmaceuticalcomposition comprising the compound of the present invention in freeform or in pharmaceutically acceptable salt form and a pharmaceuticallyacceptable carrier. In particular, the invention relates to apharmaceutical composition comprising a therapeutically effective amountof a compound of formula (I) in free form and one or morepharmaceutically acceptable carriers. In one embodiment, the inventionrelates to a pharmaceutical composition comprising a therapeuticallyeffective amount of a compound of formula (I) in pharmaceuticallyacceptable salt form and one or more pharmaceutically acceptablecarriers. In another embodiment, the invention relates to apharmaceutical composition comprising a therapeutically effective amountof a compound of formula (I) in acetate salt form and one or morepharmaceutically acceptable carriers. In yet another embodiment, theinvention relates to a pharmaceutical composition comprising atherapeutically effective amount of a compound of formula (I) inglycolate salt form and one or more pharmaceutically acceptablecarriers.

The pharmaceutical composition can be formulated for particular routesof administration such as oral administration, transdermal application,parenteral administration, rectal administration, subcutaneousadministration etc. In addition, the pharmaceutical compositions of thepresent invention can be made up in a solid form (including withoutlimitation capsules, tablets, pills, granules, powders orsuppositories), or in a liquid form (including without limitationsolutions, suspensions or emulsions). The pharmaceutical compositionscan be subjected to conventional pharmaceutical operations such assterilization and/or can contain conventional inert diluents,lubricating agents, or buffering agents, as well as adjuvants, such aspreservatives, stabilizers, wetting agents, emulsifiers and buffers,etc.

Typically, the pharmaceutical compositions are tablets or gelatincapsules comprising the active ingredient together with

-   -   a) diluents, e.g., lactose, dextrose, sucrose, mannitol,        sorbitol, cellulose and/or glycine;    -   b) lubricants, e.g., silica, talcum, stearic acid, its magnesium        or calcium salt and/or polyethyleneglycol; for tablets also    -   c) binders, e.g., magnesium aluminum silicate, starch paste,        gelatin, tragacanth, methylcellulose, sodium        carboxymethylcellulose and/or polyvinylpyrrolidone; if desired    -   d) disintegrants, e.g., starches, agar, alginic acid or its        sodium salt, or effervescent mixtures; and/or    -   e) absorbents, colorants, flavors and sweeteners.

Tablets may be either film coated or enteric coated according to methodsknown in the art.

Suitable compositions for oral administration include an effectiveamount of a compound of the invention in the form of tablets, lozenges,aqueous or oily suspensions, dispersible powders or granules, emulsion,hard or soft capsules, or syrups or elixirs. Compositions intended fororal use are prepared according to any method known in the art for themanufacture of pharmaceutical compositions and such compositions cancontain one or more agents selected from the group consisting ofsweetening agents, flavoring agents, coloring agents and preservingagents in order to provide pharmaceutically elegant and palatablepreparations. Tablets may contain the active ingredient in admixturewith nontoxic pharmaceutically acceptable excipients which are suitablefor the manufacture of tablets. These excipients are, for example, inertdiluents, such as calcium carbonate, sodium carbonate, lactose, calciumphosphate or sodium phosphate; granulating and disintegrating agents,for example, corn starch, or alginic acid; binding agents, for example,starch, gelatin or acacia; and lubricating agents, for example magnesiumstearate, stearic acid or talc. The tablets are uncoated or coated byknown techniques to delay disintegration and absorption in thegastrointestinal tract and thereby provide a sustained action over alonger period. For example, a time delay material such as glycerylmonostearate or glyceryl distearate can be employed. Formulations fororal use can be presented as hard gelatin capsules wherein the activeingredient is mixed with an inert solid diluent, for example, calciumcarbonate, calcium phosphate or kaolin, or as soft gelatin capsuleswherein the active ingredient is mixed with water or an oil medium, forexample, peanut oil, liquid paraffin or olive oil.

The compound of the invention may be administered orally to preclinicalspecies as a liquid dosage form with the drug in a solution or in asuspension vehicle. Solution vehicles can be composed of surfactant(e.g., cremophor or solutol), solvent (e.g., propylene glycol) andbuffer agent (e.g. citric buffer). Suspension formulations can containsurfactant (e.g. Tween 80), a polymer agent (e.g., methyl cellulose(MC)) and a buffer agent (e.g., phosphate).

Examples of solution formulations suitable for preclinical studies areset out below:

Ingredient (% w/w) Solution 1 Solution 2 Cremophor RH40 10 — SolutolHS15 — 10 Citric buffer 50 mM, pH 3 90 90

Preparation: free base or acetate salt(R)-7-(2-(1-(4-butoxyphenyl)-2-methylpropan-2-ylamino)-1-hydroxyethyl)-5-hydroxybenzo[d]thiazol-2(3H)-one)is first dissolved in the surfactant and mixed until a solution isobtained. Next the buffer is added and the solution mixed to provide aclear solution. Solution formulations 1 and 2 are able to support up toa 10 mg/mL dose. Both formulations are chemically and physically stableafter 1 week at RT.

Examples of suspension formulations suitable for preclinical studies areset out below:

Ingredient (% w/w) Suspension 1 Suspension 2 0.5% MC in 50 mM pH 6.8 10099.5 phosphate buffer Tween 80 — 0.5

Preparation:(R)-7-(2-(1-(4-butoxyphenyl)-2-methylpropan-2-ylamino)-1-hydroxyethyl)-5-hydroxybenzo[d]thiazol-2(3H)-one)is dispersed in the surfactant and mixed to homogenize the suspension.The polymer solution is then added drop wise and mixed. A homogeneoussuspension is obtained with small particles. The suspension ischemically and physically stable after 1 week at RT.

Certain injectable compositions are aqueous isotonic solutions orsuspensions, and suppositories are advantageously prepared from fattyemulsions or suspensions. Said compositions may be sterilized and/orcontain adjuvants, such as preserving, stabilizing, wetting oremulsifying agents, solution promoters, salts for regulating the osmoticpressure and/or buffers. In addition, they may also contain othertherapeutically valuable substances. Said compositions are preparedaccording to conventional mixing, granulating or coating methods,respectively, and contain about 0.1-75%, or contain about 1-50%, of theactive ingredient.

Suitable compositions for subcutaneous application include, for example,the compound of the invention with 2.5% poloxamer 407 in 0.9% sodiumchloride. Examples of suitable devices for injectable compositionsinclude infusion pumps such as Insulet's OmniPod system.

The compound of the invention may also be administered by multidosesubcutaneous injection using an auto injector or PEN-injector.Formulation compositions suitable for such subcutaneous injection areset out below.

Component Formulation 1 Formulation 2 Compound A 1.00 mg 1.00 mg aceticacid 0.60 mg 0.60 mg mannitol  50 mg  50 mg benzyl alcohol 8.00 mg 10.00mg  sodium hydroxide 1N adjusted to pH 5.0 adjusted to pH 5.0 water forinjection add up to 1.016 g add up to 1.016 g

Benzyl alcohol (in comparison to phenol or m-cresol) was found to be aparticularly suitable preservative for a subcutaneous injectionformulation.

Thus in one embodiment of the invention, there is provided apharmaceutical composition comprising a therapeutically effective amountof Compound A, or a pharmaceutically acceptable salt thereof (forexample Compound A in acetate salt form), and benzyl alcohol.

In a further embodiment of the invention, there is provided apharmaceutical composition comprising a therapeutically effective amountof Compound A, or a pharmaceutically acceptable salt thereof (forexample Compound A in acetate salt form), and between 0.1 and 10; 0.1and 5; 0.5 and 2; 0.5 and 1.5; or 0.9 and 1.1% (w/v) benzyl alcohol.

Suitable compositions for transdermal application include an effectiveamount of a compound of the invention with a suitable carrier. Carrierssuitable for transdermal delivery include absorbable pharmacologicallyacceptable solvents to assist passage through the skin of the host. Acombination of PG/OA (propylene glycol/oleyl alcohol) is an example ofsuitable solvent. For example, transdermal devices may be in the form ofa bandage comprising a backing member, a reservoir containing thecompound optionally with carriers, optionally a rate controlling barrierto deliver the compound of the skin of the host at a controlled andpredetermined rate over a prolonged period of time, and means to securethe device to the skin.

Suitable compositions for topical application, e.g., to the skin andeyes, include aqueous solutions, suspensions, ointments, creams, gels orsprayable formulations, e.g., for delivery by aerosol or the like. Suchtopical delivery systems will in particular be appropriate for dermalapplication. They are thus particularly suited for use in topical,including cosmetic, formulations well-known in the art. Such may containsolubilizers, stabilizers, tonicity enhancing agents, buffers andpreservatives.

As used herein a topical application may also pertain to an inhalationor to an intranasal application. They may be conveniently delivered inthe form of a dry powder (either alone, as a mixture, for example a dryblend with lactose, or a mixed component particle, for example withphospholipids) from a dry powder inhaler or an aerosol spraypresentation from a pressurised container, pump, spray, atomizer ornebuliser, with or without the use of a suitable propellant.

The present invention further provides anhydrous pharmaceuticalcompositions and dosage forms comprising the compound of the presentinvention as active ingredient, since water may facilitate thedegradation of certain compounds.

Anhydrous pharmaceutical compositions and dosage forms of the inventioncan be prepared using anhydrous or low moisture containing ingredientsand low moisture or low humidity conditions. An anhydrous pharmaceuticalcomposition may be prepared and stored such that its anhydrous nature ismaintained. Accordingly, anhydrous compositions are packaged usingmaterials known to prevent exposure to water such that they can beincluded in suitable formulary kits. Examples of suitable packaginginclude, but are not limited to, hermetically sealed foils, plastics,unit dose containers (e.g., vials), blister packs, and strip packs.

The invention further provides pharmaceutical compositions and dosageforms that comprise one or more agents that reduce the rate by which thecompound of the present invention as an active ingredient willdecompose. Such agents, which are referred to herein as “stabilizers,”include, but are not limited to, antioxidants such as ascorbic acid, pHbuffers, or salt buffers, etc.

The compound of formula (I) in free form or in pharmaceuticallyacceptable salt form, exhibits valuable pharmacological properties, e.g.beta-2-adrenoceptor modulating properties, e.g. as indicated in in vitroand in vivo tests as provided in the next sections and is thereforeindicated for therapy or for use as research chemicals, e.g. as a toolcompound.

The compound of the invention may be useful in the treatment of anindication selected from: muscular dystrophy, disuse-related atrophy,cachexia or sarcopenia.

Thus, as a further embodiment, the present invention provides thecompound of formula (I) as defined herein, as a medicament. In anembodiment, the present invention relates to the compound of formula (I)for use as a medicament. In a further embodiment, the present inventionrelates to the compound of formula (I) for use in the treatment orprevention of muscular dystrophy, disuse-related atrophy, cachexia orsarcopenia.

Thus, as a further embodiment, the present invention provides the use ofa compound of formula (I) in therapy. In a further embodiment, thetherapy is selected from a disease which may be treated by activation ofbeta-2-adrenoceptor. In another embodiment, the disease is selected frommuscular dystrophy, disuse-related atrophy, cachexia or sarcopenia.

In another embodiment, the invention provides a method of treating adisease which is treated by activation of beta-2-adrenoceptor comprisingadministration of a therapeutically acceptable amount of a compound offormula (I). In a further embodiment, the disease is selected frommuscular dystrophy, disuse-related atrophy, cachexia or sarcopenia.

A further aspect of the invention thus relates to a method of treatmentor prevention of muscular dystrophy, disuse-related atrophy, cachexia orsarcopenia comprising administering a therapeutically effective amountof a compound of formula (I) in free form or in pharmaceuticallyacceptable salt form to a subject in need thereof.

As a further embodiment, the present invention provides the use of acompound of formula (I) for the manufacture of a medicament. In afurther embodiment, the medicament is for the treatment of a disease ordisorder which may be treated by activation of beta-2 adrenoceptor. Inanother embodiment, the disease is selected from the afore-mentionedlist, suitably muscle wasting diseases, more suitably musculardystrophy, disuse-related atrophy, cachexia or sarcopenia.

The compound of the present invention may be administered eithersimultaneously with, or before or after, one or more other therapeuticagent. The compound of the present invention may be administeredseparately, by the same or different route of administration, ortogether in the same pharmaceutical composition as the other agents.

In one embodiment, the invention provides a product comprising acompound of formula (I) and at least one other therapeutic agent as acombined preparation for simultaneous, separate or sequential use intherapy. In one embodiment, the therapy is the treatment of a disease orcondition modulated by beta-2 adrenoceptor agonism. Products provided asa combined preparation include a composition comprising the compound offormula (I) and the other therapeutic agent(s) together in the samepharmaceutical composition, or the compound of formula (I) and the othertherapeutic agent(s) in separate form, e.g. in the form of a kit.

In one embodiment, the invention provides a pharmaceutical compositioncomprising a compound of formula (I) and another therapeutic agent(s).Optionally, the pharmaceutical composition may comprise apharmaceutically acceptable excipient, as described above.

A further aspect of the invention thus relates to a combinationcomprising a therapeutically effective amount of a compound of formula(I) and one or more therapeutically active co-agents.

In one embodiment, the invention provides a kit comprising two or moreseparate pharmaceutical compositions, at least one of which contains acompound of formula (I). In one embodiment, the kit comprises means forseparately retaining said compositions, such as a container, dividedbottle, or divided foil packet. An example of such a kit is a blisterpack, as typically used for the packaging of tablets, capsules and thelike.

The kit of the invention may be used for administering different dosageforms, for example, oral and parenteral, for administering the separatecompositions at different dosage intervals, or for titrating theseparate compositions against one another. To assist compliance, the kitof the invention typically comprises directions for administration.

In the combination therapies of the invention, the compound of theinvention and the other therapeutic agent may be manufactured and/orformulated by the same or different manufacturers. Moreover, thecompound of the invention and the other therapeutic may be broughttogether into a combination therapy: (i) prior to release of thecombination product to physicians (e.g. in the case of a kit comprisingthe compound of the invention and the other therapeutic agent); (ii) bythe physician themselves (or under the guidance of the physician)shortly before administration; (iii) in the patient themselves, e.g.during sequential administration of the compound of the invention andthe other therapeutic agent.

Accordingly, the invention provides the use of a compound of formula (I)for treating a disease or condition modulated by beta-2 adrenoceptoragonism, wherein the medicament is prepared for administration withanother therapeutic agent. The invention also provides the use ofanother therapeutic agent for treating a disease or condition modulatedby beta-2 adrenoceptor agonism, wherein the medicament is administeredwith a compound of formula (I).

The invention also provides a compound of formula (I) for use in amethod of treating a disease or condition modulated by beta-2adrenoceptor agonism, wherein the compound of formula (I) is preparedfor administration with another therapeutic agent. The invention alsoprovides another therapeutic agent for use in a method of treating adisease or condition modulated by beta-2 adrenoceptor agonism, whereinthe other therapeutic agent is prepared for administration with acompound of formula (I). The invention also provides a compound offormula (I) for use in a method of treating a disease or conditionmodulated by beta-2 adrenoceptor agonism, wherein the compound offormula (I) is administered with another therapeutic agent. Theinvention also provides another therapeutic agent for use in a method oftreating a disease or condition modulated by beta-2 adrenoceptoragonism, wherein the other therapeutic agent is administered with acompound of formula (I).

The invention also provides the use of a compound of formula (I) fortreating a disease or condition modulated by beta-2 adrenoceptor,wherein the patient has previously (e.g. within 24 hours) been treatedwith another therapeutic agent. The invention also provides the use ofanother therapeutic agent for treating a disease or condition modulatedby beta-2 adrenoceptor, wherein the patient has previously (e.g. within24 hours) been treated with a compound of formula (I).

In one embodiment, the other therapeutic agent is selected fromtestosterone, androgen agonists, or SARM (selective androgen receptormodulators); IGF-1 mimetics; myostatin and its receptor ActRIIA/Bblockers; TGFbeta and activin blockers (as anti-atrophy agents);Muf1/MAFbx E3 ligase inhibitors; HDAC inhibitors or any oncolytic agents(e.g. for cancer cachexia); anti-inflammatory agents like NSAIDs, TNF orIL-1b blockers; metabolic modulators like PPAR agonists or IL-15mimetics; cardiovascular agents like b(1) blockers (e.g. nebivolol) orARB (e.g. for cardiac cachexia); antisense oligos for exon-skipping(e.g. for dystrophy); an appetite enhancer such as ghrelin, progestin orMC-4 antagonists; high protein nutrient supplements and the like.

The pharmaceutical composition or combination of the present inventioncan be in unit dosage of about 0.05-1000 mg of active ingredient(s) fora subject of about 50-70 kg, or about 0.05-500 mg or about 0.05-250 mgor about 0.05-150 mg or about 0.05-100 mg, or about 0.05-50 mg or about0.05-10 mg of active ingredients. The therapeutically effective dosageof a compound, the pharmaceutical composition, or the combinationsthereof, is dependent on the species of the subject, the body weight,age and individual condition, the disorder or disease or the severitythereof being treated. A physician, clinician or veterinarian ofordinary skill can readily determine the effective amount of each of theactive ingredients necessary to prevent, treat or inhibit the progressof the disorder or disease.

The above-cited dosage properties are demonstrable in vitro and in vivotests using advantageously mammals, e.g., mice, rats, dogs, monkeys orisolated organs, tissues and preparations thereof. The compound of thepresent invention can be applied in vitro in the form of solutions,e.g., aqueous solutions, and in vivo either enterally, parenterally,advantageously subcutaneously, e.g., as a suspension or in aqueoussolution. The dosage in vitro may range between about 10⁻³ molar and10⁻⁹ molar concentrations. A therapeutically effective amount in vivomay range depending on the route of administration, between about0.01-500 mg/kg, or between about 0.01-100 mg/kg, or between about 0.01-1mg/kg, or between about 0.01-0.1 mg/kg.

The activity of the compound of the present invention can be assessed bythe following in vitro method. Further in vivo methods are describedfurther in the Examples.

Test 1: In Vitro Cellular Functional Assay Using CHO Cells and SkeletalMuscle Cells

cAMP:

Human skeletal muscle cells (skMC) were obtained from Cambrex (catalogno CC-2561) and cultured in Skeletal Basal Medium (SKBM) obtained fromCambrex (catalog no #CC-3161). The cAMP responses were measured usingcAMP dynamic 2 bulk HTRF-Assay kit obtained from Cisbio or CisCompetitive Intelligence (catalog no 62AM4PEC). skMC cells were culturedfor 1 day in SKBM cell culture medium supplemented with 20% FCS in384-well plates at 37° C., 5% CO₂. The next day, the cells were washedtwice with 50 μL PBS, and differentiated for 3 days in serum-free SKBMin presence of 1 μM SB431542, a ALK 4/5 Inhibitor obtained from Sigma(catalog no S4317) at 37° C., 7.5% CO₂. On day 4, serum-free SKBMsupplemented with 1 μM SB431542 was removed, cells were washed twicewith 50 μL PBS and further differentiated for 1 day in serum-free SKBMwithout SB431542 (50 μL per well) at 37° C., 7.5% CO₂. Rat skMC andcardiomyocytes cells were isolated from neonatal rats in a standard wayand treated as described above. Chinese hamster ovary (CHO) cells stablytransfected with human β adrenoceptors (β1 or β2) were produced atNovartis Institutes for BioMedical Research and cultured as describedbefore (J Pharmacol Exp Ther. 2006 May; 317(2):762-70).

Compounds were made up in stimulation buffer at 2× requiredconcentration and 1:10 serial dilutions in stimulation buffer wereprepared in 96-well plate (U-form). DMSO control was normalized to theDMSO content of the highest dilution, e.g. 0.1% DMSO (×2) for 10⁻⁵ M(×2) concentration of the first compound dilution. The assay was carriedout in 384-well plates, in a 20 μL stimulation volume, and a final assayvolume of 40 μL per well. On the day of experiment, culture medium wasremoved from 384-well cell culture plates by inverting and flicking theplate on stack of paper 2-3 times. 10 μL of fresh culture medium perwell was first added in the 384-well plate. After 10 minutes ofincubation at room temperature, 10 μL per well of working compoundsdilutions were added to the cells and incubated for 30 minutes at roomtemperature in the dark. During this time, working solutions of reagentswere prepared by diluting stock solutions of anti cAMP cryptate and cAMPD2 1:20 in lysis buffer, supplied with the kit. After 30 minutes ofcompound incubation, 10 μL of cAMP-D2 and 10 μL of anti cAMP cryptatewere sequentially added to the assay plates. After 1 hour of incubationtime at room temperature in the dark, the measurement was performed withthe PheraStar (Excitation wavelength: 337 nm, Emission wavelengths: 620and 665 nm).

Ca²⁺:

The human adrenergic Alpha1A CHO-K1 cell line was purchased from PerkinElmer (ValiScreen™ Stable recombinant GPCR Cell line, catalog noES-036-C, Lot no M1W-C1, Boston, Mass., USA). One day before theexperiment, Alpha1A frozen cells (10 millions per ml and per vial) werethawed in a water bath at 37° C. The cell suspension was centrifuged for5 minutes at 1,000 rpm and the cell pellet was resuspended in cellculture medium. Cells were seeded into black 384-well plates with clearbottom at a density of 8,000 cells per well in 50 μL of cell culturemedium. Plates were incubated for about 24 hours at 37° C., 5% CO₂. Theday of the experiment, the medium was removed using a cell washer (TECANPW3). After the final wash there was 10 μL left in the wells. 40 μL ofloading buffer were added and cells were loaded for 60 min at 37° C., 5%CO₂. Plates were washed with TECAN PW3 with 20 μL assay buffer left andwere incubated for at least 20 minutes at RT before performing the FLIPRexperiment. Compounds were then characterized in the agonist and/orantagonist mode. For assay validation, the same protocol was used withthe fresh cells. In this case, cells were detached from a 150 cm² flaskusing 3 ml of Trypsin-EDTA, centrifuged and resuspended in cell culturemedium.

Cells were stimulated by adding 5 μL of compounds (5×), using the FLIPRhead. Compounds acting as agonists induce a transient increase ofintracellular calcium. This was recorded on the FLIPR system. Ameasurement of the signal baseline was first recorded every second for 2minutes before the injection of the compounds. Calcium measurements wereperformed by exciting the cells with the argon ion laser at 488 nm at0.6 W laser power and recording the fluorescence signal with a CCDcamera (opening of 0.4 sec) for 2 minutes. Low controls (unstimulatedcells) were determined with the addition of 5 μL of assay buffer. Highcontrols were determined with the addition of 5 μL of a known agonist athigh concentration EC₁₀₀ (A-61603 at 1 μM) and a reference agonistcompound was also added in each plate.

The compound of the invention exhibits efficacy in test assay 1 with anEC₅₀ of less than 10 nM. Specific activity is shown in example 10

Further specific activities of the compound of the invention aredescribed in examples 11 to 15.

The following examples are intended to illustrate the invention and arenot to be construed as being limitations thereon. Temperatures are givenin degrees Celsius. If not mentioned otherwise, all evaporations areperformed under reduced pressure, typically between about 15 mm Hg and100 mm Hg (=20-133 mbar). The structure of final products, intermediatesand starting materials is confirmed by standard analytical methods,e.g., microanalysis and spectroscopic characteristics, e.g., MS, IR,NMR. Abbreviations used are those conventional in the art.

All starting materials, building blocks, reagents, acids, bases,dehydrating agents, solvents, and catalysts utilized to synthesise thecompound of the present invention are either commercially available orcan be produced by organic synthesis methods known to one of ordinaryskill in the art (Houben-Weyl 4th Ed. 1952, Methods of OrganicSynthesis, Thieme, Volume 21). Further, the compound of the presentinvention can be produced by organic synthesis methods known to one ofordinary skill in the art as shown in the following examples.

EXAMPLES

List of Abbreviations

-   1M one molar-   APCI atmospheric-pressure chemical ionization-   aq aqueous-   AR adrenoceptor-   atm atmosphere-   br broad-   cm centimeters-   d doublet-   dd double doublet-   ddd double double doublet-   (DHDQ)₂PHAL Hydroquinidine 1,4-phthalazinediyl diether-   DMAC dimethylacetamide-   DMSO dimethylsulfoxide-   DSC differential scanning calorimetry-   ee enantiomeric excess-   equiv equivalent-   ES electron-spray-   g grams-   h hours-   HPLC high performance liquid chromatography-   HRMS high resolution mass spectroscopy-   m multiplet-   MC methyl cellulose-   mbar millibar-   MeOH methanol-   min minutes-   ml milliliters-   MS mass spectroscopy-   MTBE methyl tert-butyl ether-   nm nanometers-   NMR nuclear magnetic resonance-   RT retention time-   r.t. room temperature-   s singlet-   sat. saturated-   sept septet-   t triplet-   TFA trifluoroacetic acid-   μm micrometers-   w/v weigh/volume-   XRPD x-ray powder diffraction

Unless otherwise indicated, HPLC/MS spectra were recorded on an Agilent1100 series LC/Agilent MS 6210 Quadrupole. A Waters Symmetry C8 column(3.5 um; 2.1×50 mm) (WAT200624) was used. The following gradient methodwas applied (%=percent by volume): A=water+0.1% TFA/B=acetonitrile+0.1%TFA; 0.0-2.0 min 90A:10B-5A:95B; 2.0-3.0 min 5A:95B; 3.0-3.3 min5A:95B-90A:10B; flow 1.0 ml/min; column temperature 50° C. All compoundswere ionized in APCI mode.

¹H-NMR spectra were recorded on a Varian Mercury (400 MHz) or BrukerAdvance (600 MHz) machine.

Optical rotation was measured on a Perkin Elmer Polarimeter 341.

LCMS Condition for Example 2b, 2c, 2d, 2e, 2g:

Mass spectra station: Agilent 6130 quadrupole LC/MS with Agilent 1200HPLC; Column: Agilent Zorbax SB-C18 (Rapid resolution), 2.1*30 mm, 3.5μm; Mobile phases: B: 0.1% formic acid in water; C, 0.1% formic acid inMeCN; 1.0 min to 6.0 min, 95% B to 5% B, and 5% C to 95% C, 6.0 min to9.0 min, 5% B and 95% C; post time: 2.0 min; flow rate: 0.8 ml/min;column temperature: 30° C.; UV detection: 210 nm and 254 nm; MS scanpositive and negative: 80-1000; Ionization method: API-ES.

HRMS Conditions for Example 2f:

Instrument: Waters Acquity UPLC coupled with Synapt Q-TOF MS; Column:Waters Acquity UPLC BEH C18, 2.1*50 mm, 1.7 μm Mobile Phase: A: 0.1%formic acid in water, B: 0.1% formic acid in Acetonitrile; Columntemperature: at room temperature; UV detection: scan from 190 nm to 400nm; Flow rate: 0.5 mL/min;

Gradient Condition:

Time Phase B [min.] [%] 0 5 1 5 Start of acquisition 9 95 11 95 End ofacquisition 11.10 5 14 5 Next injection Ionization method: ESI+; MS scanrange: 100-1000 m/z.

Intermediate A: 2-(4-butoxyphenyl)-1,1-dimethyl-ethylamine a)4-(2-methyl-2-nitropropyl)phenol

A mixture of 4-(hydroxymethyl)phenol (20 g), KOtBu (27.1 g) and DMAC(200 mL) was stirred with magnetic stirrer. 2-nitropropane (21.5 g) wasadded slowly within 20 min. The mixture was heated to 140° C. for 5 hrbefore cooled to r.t. The mixture was added slowly to cool HCl aqueoussolution (3.0%, 600 mL), then extracted with MTBE (300 ml*1, 200 m1*1).The organic layers were combined, washed with water (300 ml*2) and sat.NaCl aqueous solution (50 ml*1), then dried with anhydrous Na₂SO₄. Themixture was filtered and concentrated under vacuum to give light-yellowsolid (28.5 g), which was used for next step without furtherpurification.

[M−1]⁺=194.2; RT=5.3 minutes

¹H-NMR (400 MHz, CDCl₃) ppm 6.96 (d, J=8.5 Hz, 2H), 6.75 (d, J=8.5 Hz,2H), 3.11 (s, 2H), 1.56 (s, 6H).

b) 1-butoxy-4-(2-methyl-2-nitropropyl)benzene

The mixture of 4-(2-methyl-2-nitropropyl)phenol (20.4 g), 1-bromobutane(28.7 g), DMAC (200 ml), K₂CO₃ (21.6 g), tetrabutylammonium iodide (38.7g) was stirred with magnetic stirrer and heated to 85° C. for 17 h. Themixture was cooled to 0-10° C. and water (700 ml) was added. The mixturewas extracted with MTBE (300 ml*1, 200 ml*1). The combined organicphases were washed with water (250 ml*2), then concentrated under vacuumto give a red-brown oil (27.8 g), which was used in the next stepwithout further purification.

¹H-NMR (400 MHz, CDCl₃) ppm 7.0 (d, J=8.8 Hz, 2H), 6.81 (d, J=8.8 Hz,2H), 3.93 (t, J=6.6 Hz, 2H), 3.12 (s, 2H), 1.74 (m, 2H), 1.56 (s, 6H),1.48 (m, 2H), 0.97 (t, 3H).

c) 2-(4-butoxyphenyl)-1,1-dimethyl-ethylamine

In a hydrogenating reactor (1 L), a solution of1-butoxy-4-(2-methyl-2-nitropropyl)benzene (27.8 g) in AcOH (270 ml) wasadded followed by wet Raney Ni (7.0 g). The mixture was purged with H₂for 3 times, then heated to 60° C. and kept stirring under 5.0 atm for16 h. The mixture was filtered, the total filtrate was concentratedunder vacuum. The resulting residue was diluted with water (150ml)/n-heptane (80 ml), the aqueous layer was washed with n-heptane (80ml) again. The aqueous layer was adjusted with NaOH (˜20%) to pH˜11,then extracted with MTBE (100 ml*1) and EtOAc (150 ml*2). The mediumlayer was discarded. All top layers were combined and washed withsaturated NaHCO₃ (100 ml) and saturated NaCl (100 ml) before being driedwith anhydrous Na₂SO₄. After filtration, the mixture was concentrated.The resulting residual was stirred and HCl solution in isopropyl alcohol(2M, 40 ml) was added. The slurry was heated to 60° C. and n-heptane(120 ml) was added. The mixture was cooled to 20° C., then filtered, thecake was washed with some n-heptane. The white solid was dried in airfor 2 days to give 10 g of pure HCl salt of product. Yield: 35.2%.

[MH]+=222.2; RT=5.0 minutes

¹H-NMR (400 MHz, d-DMSO) ppm 8.13 (s, 3H), 7.12 (d, J=8.6 Hz, 2H), 6.88(d, J=8.5 Hz, 2H), 3.93 (t, J=6.4 Hz, 2H), 2.80 (s, 2H), 1.67 (m, 2H),1.42 (m, 2H), 1.18 (s, 6H), 0.92 (t, 3H).

EXAMPLE 1(R)-7-(2-(1-(4-butoxyphenyl)-2-methylpropan-2-ylamino)-1-hydroxyethyl)-5-hydroxybenzo[d]thiazol-2(3H)-one

a) 1-tert-Butoxy-3-fluoro-5-isothiocyanatobenzene

Thiophosgene (33.6 g) in CHCl₃ (250 ml) and K₂CO₃ (64.7 g) in H₂O (450ml) are added, separately and simultaneously, drop wise to a solution of3-tert-Butoxy-5-fluoro-phenyl-amine (42.9 g) in CHCl₃ (350 ml) at 0° C.The reaction mixture is warmed to room temperature over night. Theorganics are separated and washed with water (3×), brine (1×), driedover MgSO₄, filtered and the solvent removed in vacuo. The titlecompound is obtained by flash column chromatography (silica, eluentdichloromethane/iso-hexane 1:3).

¹H NMR (CDCl₃, 400 MHz); 6.70 (m, 3H), 1.40 (s, 9H).

b) (3-tert-Butoxy-5-fluoro-phenyl)-thiocarbamic acid O-isopropyl ester

1-tert-Butoxy-3-fluoro-5-isothiocyanatobenzene (24.0 g) andtriethylamine (10.9 g) are dissolved in iso-propanol (150 ml). Thereaction mixture is refluxed for 18 hours and the solvent is removed byvacuo. The crude product is dissolved in hexane: diethyl ether (19:1).The diethyl ether is removed in vacuo and the solution is cooled to 0°C. for 3 hours. The solution is filtered to give the title compound.

¹H NMR (CDCl₃, 400 MHz); 8.10 (br s, 1H), 6.65 (br s, 2H), 6.45 (ddd,1H) 5.60 (sept, 1H), 1.35 (d, 6H), 1.30 (s, 9H).

c) 5-tert-Butoxy-2-isopropoxy-benzothiazole-7-carbaldehyde

(3-tert-Butoxy-5-fluoro-phenyl)-thiocarbamic acid O-isopropyl ester (2.2g) is dissolved in dry tetrahydrofuran (20 ml) The reaction mixture iscooled to −78° C. and tert-butyl lithium (15.2 ml, of 1.5 M solution) isadded over 20 minutes. The reaction mixture is then warmed to −10° C.for 75 minutes. The reaction mixture is then re-cooled to −78° C.,N,N-dimethyl-formamide (1.5 g) is added and the reaction mixture isslowly warmed to room temperature then stirred at −10° C. for 1 hour.The reaction mixture is quenched with HCl_((aq)) (5 ml, of a 2 Msolution), the organics are separated between ethyl acetate/water andremoved in vacuo. The title compound is obtained by flash columnchromatography (silica, eluent ethyl acetate/iso-hexane 1:9).

MS (ES+) m/e 294 (MH⁺).

d) 5-tert-Butoxy-2-isopropoxy-7-vinylbenzothiazole

Ph₃PMe.Br (5.0 g) is dissolved in dry tetrahydrofuran (100 ml) underargon. N-butyl lithium (8.8 ml, of 1.6 M solution) is added at roomtemperature over 10 minutes and reaction mixture stirred for a further30 minutes. A solution of5-tert-Butoxy-2-isopropoxy-benzothiazole-7-carbaldehyde (1.25 g) indichloromethane (40 ml) is added drop wise to the reaction mixture andthe reaction mixture is stirred for 4.5 hours at room temperature. Thesolvent is removed in vacuo, redissolved in ethyl acetate, washed withwater (3×), brine (1×), dried over MgSO₄, filtered and the solventremoved in vacuo. The title compound is obtained by flash columnchromatography (silica, eluent ethyl acetate/iso-hexane 1:9).

MS (ES+) m/e 292 (MH⁺).

e) (R)-1-(5-tert-Butoxy-2-isopropoxy-benzothiazol-7-yl)-ethane-1,2-diol

K₃Fe(CN)₆ (1.2 g), K₂CO₃ (0.5 g), (DHQD)₂PHAI (19 mg) are dissolved intert-butanol/water (15 ml, 1:1 mix) under argon and stirred for 15minutes. The reaction mixture is cooled to 0° C. and OsO₄ (3.1 mg) isadded followed by 5-tert-Butoxy-2-isopropoxy-7-vinylbenzothiazole (0.35g). The reaction mixture is stirred over night at room temperature. Thereaction mixture is quenched with sodium-meta-bisulphate (1 g) andstirred for 1.5 hours. Ethyl acetate is added, the organics areseparated, washed with (2×) water, (1×) brine, dried over MgSO₄,filtered and the solvent removed in vacuo. The title compound isobtained by flash column chromatography (silica, eluent ethylacetate/iso-hexane 2:5).

MS (ES+) m/e 326 (MH⁺).

f)(R)-2-(5-tert-butoxy-2-isopropoxybenzo[d]thiazol-7-yl)-2-hydroxyethyl-4-methylbenzenesulfonate

Into a 500-ml 3-necked round-bottom flask, purged and maintained with aninert atmosphere of nitrogen, was placed a solution of(R)-1-(5-tert-butoxy-2-isopropoxy-benzo[d]thiazol-7-yl)ethane-1,2-diol(20 g, 59.05 mmol) in pyridine (240 ml) and 4 Å molecular sieves (5 g).This was followed by the addition of a solution of toluenesulfonic acidchloride (tosyl chloride) (15.3 g, 79.73 mmol) in pyridine (60 ml)dropwise with stirring at 0° C. The resulting solution was stirred for 4h at room temperature. The reaction was then quenched by the addition of1000 ml of 1M hydrogen chloride. The resulting solution was extractedwith 2×300 ml of ethyl acetate and the organic layers are combined. Theorganic phase was washed with 1×500 ml of 1M hydrogen chloride, 1×500 mlof 10% sodium bicarbonate and 300 ml of brine. The mixture was driedover anhydrous sodium sulfate and concentrated under vacuum. The residuewas applied onto a silica gel column with ethyl acetate/petroleum ether(1:10). This resulted in 26 g (87%) of(R)-2-(5-tert-butoxy-2-isopropoxybenzo[d]thiazol-7-yl)-2-hydroxyethyl4-methylbenzenesulfonate as yellow oil.

LC/MS R_(T)=2.47 min; (m/z): 480 [M+H]⁺

¹H-NMR: (400 MHz, DMSO-d₆): δ (ppm) 7.57 (d, 2H); 7.36 (d, 2H); 7.17 (d,1H); 6.79 (d, 1H); 6.32 (d, 1H); 5.37-5.26 (m, 1H); 4.97-4.90 (m, 1H);4.12-4.00 (m, 2H); 2.40 (s, 3H); 1.45-1.38 (m, 6H); 1.32 (s, 9H).

q)(R)-1-(5-tert-butoxy-2-isopropoxybenzo[d]thiazol-7-yl)-2-(1-(4-butoxyphenyl)-2-methylpropan-2-ylamino)ethanol

Into a 1000-mLml 4-necked round-bottom flask was placed a solution of(R)-2-(5-tert-butoxy-2-isopropoxybenzo[d]thiazol-7-yl)-2-hydroxyethyl-4-methylbenzenesulfonate(26 g, 51.55 mmol, 1.00 equiv) in toluene (320 mLml) and2-(4-butoxyphenyl)-1,1-dimethyl-ethylamine (intermediate A) (22 g, 99.47mmol, 1.93 equiv). The solution was stirred for 24 h at 90° C. in an oilbath. The resulting mixture was concentrated under vacuum. The residueis applied onto a silica gel column with ethyl acetate/petroleum ether(1:8). This resulted in 16 g (58%) of(R)-1-(5-tert-butoxy-2-isopropoxybenzo[d]thiazol-7-yl)-2-(1-(4-butoxyphenyl)-2-methylpropan-2-ylamino)ethanolas light yellow oil.

LC/MS: R_(T)=2.24 min (m/z): 529 [M+H]⁺

¹H-NMR: (600 MHz, DMSO-d₆): δ (ppm) 7.12 (s, 1H); 6.83 (d, 2H); 6.77 (s,1H); 6.63 (d, 2H); 5.80 (br. s, 1H); 5.38-5.30 (m, 1H); 4.70-4.66 (m,1H); 3.90 (t, 2H); 2.81-2.61 (m, 2H); 2.50-2.39 (m, 2H); 1.71-1.62 (m,2H); 1.47-1.41 (m, 2H); 1.41 (d, 6H); 1.22 (s, 9H); 0.91 (q, 3H); 0.88(s, 3H); 0.83 (s, 3H).

h)(R)-7-(2-(1-(4-butoxyphenyl)-2-methylpropan-2-ylamino)-1-hydroxyethyl)-5-hydroxybenzo[d]thiazol-2(3H)-one

A solution of(R)-1-(5-tert-butoxy-2-isopropoxybenzo[d]thiazol-7-yl)-2-(1-(4-butoxyphenyl)-2-methylpropan-2-ylamino)ethanol(3.5 g) in formic acid (40 ml) was stirred for 68 h at ambienttemperature. 50 ml of water was added, and the resulting mixture wasevaporated to dryness (rotary evaporator, 15 mbar, 40° C.) to give 3.8 gof crude product. This material was partitioned between saturatedaqueous sodium bicarbonate (50 ml) and ethyl acetate (50 ml) in order toremove formic acid. The aqueous layer was extracted 3× with ethylacetate (30 ml each). The combined organic extracts were dried overmagnesium sulfate, filtered and concentrated to give 3 g of crudefree-base. This material was flash-chromatographed (silica gel; gradient0-60% methanol in dichloromethane). Pure fractions were collected andevaporated to dryness to give 1.74 g of an amorphous semi-solid.

This material was subjected to chiral preparative chromatography[column: Chiralpak IC (20 um) 7.65×37.5 cm; eluent:n-heptane/dichloromethane/ethanol/diethylamine 50:30:20 (+0.05diethylamine); flow rate=70 ml/min; concentration: 2.5 g/50 ml eluent;detection: UV, 220 nm] to give pure enantiomer (100% ee).

This material was dissolved in 45 ml of acetonitrile at 60° C. Thesolution was allowed to cool to ambient temperature over 18 h, uponwhich precipitation occurred. The mixture was diluted with 5 ml of cold(4° C.) acetonitrile and filtered through a Buchner funnel. The filtercake was washed twice with cold acetonitrile. Then the wet solid wascollected and dried in vacuo (0.2 mbar) at ambient temperature overnightto give 1.42 g of(R)-7-(2-(1-(4-butoxyphenyl)-2-methylpropan-2-ylamino)-1-hydroxyethyl)-5-hydroxybenzo[d]thiazol-2(3H)-oneas a colorless powder.

LC/MS: R_(T)=1.81 min (m/z): 431 [M+H]⁺

¹H-NMR: (600 MHz, DMSO-d₆): δ (ppm) 11.5 (br. s, 1H); 9.57 (br. s, 1H);6.99 (d, 2H); 6.76 (d, 2H); 6.52 (s, 1H); 6.47 (s, 1H); 5.63 (br. s,1H); 4.53-4.48 (m, 1H); 3.90 (t, 2H); 2.74-2.63 (m, 2H); 2.54-2.45 (m,2H); 1.71-1.62 (m, 2H); 1.49-1.40 (m, 2H); 0.93 (q, 3H); 0.89 (s, 6H).

Optical rotation: [α]_(D) ²²=−43° (c=1.0 g/100 ml MeOH).

EXAMPLE 2 alternative route to(R)-7-(2-(1-(4-butoxyphenyl)-2-methylpropan-2-ylamino)-1-hydroxyethyl)-5-hydroxybenzo[d]thiazol-2(3H)-one

a) 1-tert-Butoxy-3-fluoro-5-isothiocyanato-benzene

1,1′-Thiocarbonyldiimidazole (423 g, 2.37 mol) was dissolved indichloromethane (3200 ml). The mixture was stirred under N₂ atmospherewhile a solution of 3-tert-butoxy-5-fluoroaniline (435 g, 2.37 mol) indichloromethane (800 ml) was added slowly within 2 h. Then the mixturewas kept stirring at 20° C. for 16 h. The mixture was diluted with water(3000 ml). The separated dichloromethane phase was washed again withwater (3000 ml) before dried with anhydrous Na₂SO₄ for 2 h. The mixturewas filtered and the filtrate was concentrated under vacuum to removesolvent to give 1-tert-butoxy-3-fluoro-5-isothiocyanato-benzene (499 g).

¹H-NMR (400 MHz, CDCl₃): 6.63-6.68 (m, 3H), 1.37 (s, 9H).

b) (3-tert-Butoxy-5-fluoro-phenyl)-thiocarbamic acid O-isopropyl ester

To a solution of 1-tert-butoxy-3-fluoro-5-isothiocyanatobenzene (460 g,2.04 mol) in anhydrous isopropyl alcohol (3250 ml) was addedtriethylamine (315 g, 3.06 mol). The mixture was heated to reflux underN₂ atmosphere for 16 h and the temperature was cooled to 40-50° C. Afterconcentration, the resulting dark residue was diluted with n-heptane(1000 ml) and heated to 60° C. The mixture was slowly cooled to 25° C.,at the same time seeding was added. A slurry was observed and stirred at25° C. for 16 h before being cooled slowly to 0-10° C. within 2 h. Afterfiltration and washing with n-heptane (200 ml), the collected solid wasdried in oven under vacuum at 40-45° C. for 18 h to give(3-tert-Butoxy-5-fluoro-phenyl)-thiocarbamic acid O-isopropyl ester(453.1 g).

LCMS: [M+H]⁺=286.1; RT=7.2 minutes

¹H-NMR (400 MHz, CDCl₃): 8.18 (s, 1H), 6.81 (m, 2H), 6.51 (dt, J=10.2Hz, 1H), 5.66 (heptet, J=6.3 Hz, 1H), 1.42 (d, J=6.2 Hz, 6H), 1.37 (s,9H).

c) 1-(5-tert-Butoxy-2-isopropoxy-benzothiazol-7-yl)-2-chloro-ethanone

Under a nitrogen atmosphere, a solution of tert-butyllithium (481 ml,737.6 mmol, 1.6 M) was added dropwise to a solution of(3-tert-Butoxy-5-fluoro-phenyl)-thiocarbamic acid O-isopropyl ester (200g, 700.83 mmol) in 2-Me-THF (1600 ml) at temperature below −65° C. Thereaction temperature was warmed to −35° C., and a second portion oftert-butyllithium (388 ml, 737.6 mmol, 1.9 M) was added slowly whilekeeping the temperature below −35° C. The reaction mixture was thenstirred at this temperature for 3 h and cooled down to −70° C. Asolution of N-methyl-N-methoxy chloroacetamide (96.4 g, 700.83 mmol) in2-MeTHF (300 ml) was added to the reaction mixture while keeping thetemperature below −70° C. The mixture was then warmed to −30° C. andstirred for 45 minutes. The cold reaction mixture was quenched bydropwise addition of 30% HCl in isopropanol (240 g) followed by theaddition of 1500 ml water. The organic layer was washed sequentiallywith 1000 ml water, 1500 ml saturated aqueous NaHCO₃ and 1500 ml brine.After concentration, the resulting light brown residue was added toisopropanol (135 ml). The mixture was warmed to 50° C. and cooled downslowly to 25° C. n-heptane (135 ml) was added dropwise to the solutionand the mixture was stirred overnight. The slurry was filtered and thefilter cake was washed with n-heptane (40 ml) followed by anotherportion of n-heptane (20 ml). The cake was dried under vacuum to yield1-(5-tert-butoxy-2-isopropoxy-benzothiazol-7-yl)-2-chloro-ethanone asoff-white powder (42.8 g, 17.9% yield).

¹H NMR (400 MHz, CDCl₃): 7.60 (d, J=2.0 Hz, 1H), 7.45 (d, J=2.0 Hz, 1H),5.40 (heptet, J=6.3 Hz, 1H), 4.77 (s, 2H), 1.47 (d, J=6.3 Hz, 6H), 1.40(s, 9H).

LCMS: [M+H]⁺=342.1, RT=7.29 min.

d) (R)-1-(5-tert-Butoxy-2-isopropoxy-benzothiazol-7-yl)-2-chloro-ethanol

A suspension of1-(5-tert-butoxy-2-isopropoxybenzo[d]thiazol-7-yl)-2-chloro-ethanone (70g, 204.8 mmol) and RuCl(p-cymene)[(S,S)-Ts-DPEN] (1.954 g, 3.07 mmol) inmethanol/DMF (1330 ml/70 ml) was degassed and refilled with N₂ threetimes. A degassed preformed mixture of formic acid (28.3 g) in Et₃N(124.3 g) was added slowly while keeping the internal temperaturebetween 15 to 20° C. The resulting yellow suspension was warmed up to30° C. After 2 h the reaction mixture is cooled to 25° C., water (750ml) was then added into the reaction mixture followed by the addition ofacetic acid (56 ml) in one portion. The mixture was concentrated andthen diluted with TBME (1000 ml). Aqueous phase was separated andextracted with TBME (1000 ml). The combined organic phase was washedsequentially with water and brine and then dried with Na₂SO₄ andconcentrated under vacuum to give(R)-1-(5-tert-Butoxy-2-isopropoxy-benzothiazol-7-yl)-2-chloro-ethanol(72 g).

LCMS (method A): [M+H]⁺=343.1, RT=5.67 min.

¹H NMR (400 MHz, CDCl₃): 7.29 (d, J=2.0 Hz, 1H), 6.83 (d, J=2.0 Hz, 1H),5.37 (heptet, J=6.3 Hz, 1H), 4.96 (m, 1H), 3.74 (m, 2H), 3.01 (s, 1H),1.46 (d, J=6.2 Hz, 6H), 1.36 (s, 9H).

e) (R)-5-tert-Butoxy-2-isopropoxy-7-oxiranyl-benzothiazole

To a solution of(R)-1-(5-tert-butoxy-2-isopropoxybenzo[d]thiazol-7-yl)-2-chloro-ethanol(140 g, 407.1 mmol) in TBME (420 ml) was added dropwise NaOH aqueoussolution (2M, 420 ml) followed by tetrabutylammonium iodide (7.52 g,20.36 mmol) added in one portion. After 4 h at 26° C., 400 ml TBME wasadded and the organic layer was separated. The aqueous layer wasextracted with TBME (400 ml). The combined organic layers were washedwith water (400 ml) and brine (400 ml) to give(R)-5-tert-butoxy-2-isopropoxy-7-oxiranyl-benzothiazole (122 g).

LCMS: [M+H]⁺=308.0, RT=6.80 min.

¹H NMR (400 MHz, CDCl₃) ppm 7.28 (d, J=2.0 Hz, 1H), 6.85 (d, J=2.0 Hz,1H), 5.38 (m, 1H), 3.96 (m, 1H), 3.15 (dd, J=4.3, 5.5 Hz, 1H), 2.94 (dd,J=4.3, 5.5 Hz, 1H), 1.45 (d, J=Hz, 6H), 1.37 (s, 9H).

f)(R)-1-(5-tert-butoxy-2-isopropoxybenzo[d]thiazol-7-yl)-2-(1-(4-butoxyphenyl)-2-methylpropan-2-ylamino)ethanol

(R)-5-tert-butoxy-2-isopropoxy-7-oxiranyl-benzothiazole (145 g, 471.7mmol) and 2-(4-butoxy-phenyl)-1,1-dimethyl-ethylamine (114.8 g, 518.9mmol) were dissolved in DMSO (850 ml). The reaction mixture was heatedto 80° C. and stirred for 27 h. The mixture was then cooled to 25° C.and added to a stirred mixture of water (1500 ml) and TBME (1500 ml).The aqueous layer was separated and extracted with TBME (1000 ml). Thecombined organic layers were sequentially washed with water (1500 ml)and brine (1000 ml), dried with anhydrous Na₂SO₄. After concentration,the residue was purified by column chromatography (eluting with 10% ofEtOAc in n-heptane to 33% of EtOAc in n-heptane). Solid product(R)-1-(5-tert-butoxy-2-isopropoxybenzo[d]thiazol-7-yl)-2-(1-(4-butoxyphenyl)-2-methylpropan-2-ylamino)ethanolwas obtained (140 g) as off-white solid.

HRMS: [M+1] 529.2996

¹H NMR (400 MHz, CDCl₃): 7.26 (m, 1H), 7.01 (m, 1H), 6.99 (m, 1H),6.78-6.80 (m, 3H), 5.39 (m, 1H), 4.65 (dd, J=3.8, 8.8 Hz, 1H), 3.83 (t,J=6.4 Hz, 2H), 2.96 (dd, J=3.8, 12 Hz, 1H), 2.74 (dd, J=8.8, 12 Hz, 1H),2.60 (dd, J=13.6, 17.6 Hz, 2H), 1.72-1.79 (m, 2H), 1.50 (m, 2H), 1.46(d, J=2.0 Hz, 3H), 1.45 (d, J=2.0 Hz, 3H), 1.35 (s, 9H), 1.06 (s, 3H),1.04 (s, 3H), 0.98 (t, J=7.2 Hz, 3H).

g)(R)-7-(2-(1-(4-butoxyphenyl)-2-methylpropan-2-ylamino)-1-hydroxyethyl)-5-hydroxybenzo[d]thiazol-2(3H)-one

To(R)-1-(5-tert-butoxy-2-isopropoxybenzo[d]thiazol-7-yl)-2-(1-(4-butoxyphenyl)-2-methylpropan-2-ylamino)ethanol(7.5 g) in isopropanol (30 ml) and water (25 ml) was added 1M HClaqueous solution (43 ml). The reaction mixture was then heated to 60° C.and stirred for 2.5 h. The mixture was cooled to 50° C., and then 2MNaOH aqueous solution (18 ml) was added slowly to adjust pH between8.2-8.4. The reaction mixture was then cooled to 30° C., followed byextraction with TBME (first time with 40 ml, the second time with 25ml). Two organic layers were combined and washed with water (38 ml fortwo times) before drying with anhydrous Na₂SO₄. After filtration, thefiltrate was concentrated, and then dissolved in MeCN (145 ml). Thesolution was treated with active carbon (0.6 g) and heated to 60° C.After a second filtration, the cake was washed with MeCN (10 ml for twotimes), the filtrate was crystallized at 60° C. to gain(R)-7-(2-(1-(4-butoxyphenyl)-2-methylpropan-2-ylamino)-1-hydroxyethyl)-5-hydroxybenzo[d]thiazol-2(3H)-one(3.8 g). e.e. =97.6%.

LCMS (method A): [M+H]⁺=431.2

¹H NMR (400 MHz, DMSO-d₆): 9.5 (br. s, 1H), 6.81 (d, J=8.5 Hz, 2H), 6.57(d, J=8.6 Hz, 2H), 6.33 (d, J=2.2 Hz, 1H), 6.30 (d, J=2.2 Hz, 1H), 4.43(br. s, 1H), 3.69 (t, J=6.4 Hz, 2H), 2.58-2.59 (m, 2H), 2.24-2.31 (m,2H), 1.41-1.48 (m, 2H), 1.15-1.25 (m, 2H), 0.78 (s, 6H), 0.70 (t, J=7.4Hz, 3H).

EXAMPLE 3(R)-7-(2-(1-(4-butoxyphenyl)-2-methylpropan-2-ylamino)-1-hydroxyethyl)-5-hydroxybenzo[d]thiazol-2(3H)-oneacetate salt

500 mg (1.161 mmol) of free base(R)-7-(2-(1-(4-butoxyphenyl)-2-methylpropan-2-ylamino)-1-hydroxyethyl)-5-hydroxybenzo[d]thiazol-2(3H)-onewas suspended in 10.0 ml acetonitrile and 0.25 ml water in a 50 mlfour-necked flask and paddle stirred at r.t. The suspension was heatedat an internal temperature of 50° C. (jacket temperature 75° C.) and 72mg acetic acid (1.161 mmol) was added (a clear yellow solution wasformed). The solution was cooled down over 30 min. at r.t. and 0.15 mlwater added.

The solution was then seeded with(R)-7-(2-(1-(4-butoxyphenyl)-2-methylpropan-2-ylamino)-1-hydroxyethyl)-5-hydroxybenzo[d]thiazol-2(3H)-oneacetate and stirred overnight (16 h) at r.t. The suspension was thenfiltered at r.t. through a glass filer and washed three times with 1 mlacetonitrile. 510 mg of wet filter cake was dried in a drying ovenovernight (16 h) at r.t. to dryness. Yield: 508 mg white powder (89.1%)

Preparation of(R)-7-(2-(1-(4-butoxyphenyl)-2-methylpropan-2-ylamino)-1-hydroxyethyl)-5-hydroxybenzo[d]thiazol-2(3H)-oneacetate seeds

57.0 mg (0.132 mmol) of free base(R)-7-(2-(1-(4-butoxyphenyl)-2-methylpropan-2-ylamino)-1-hydroxyethyl)-5-hydroxybenzo[d]thiazol-2(3H)-oneand 8.03 mg (0.132 mmol) acetic acid were dissolved in 1.0 mlacetonitrile and 0.05 ml water. The solution was stirred at r. t. with amagnetic stirrer stirred. Precipitation took place over night. Thesolution was then filtered at r.t. through a glass filter and washedthree times with 0.5 ml acetonitrile. The wet filter cake was dried in adrying oven overnight (16 h) at r. t. to dryness. Yield: 57 mg whitepowder

EXAMPLE 3a Alternative procedure for the formation of(R)-7-(2-(1-(4-butoxyphenyl)-2-methylpropan-2-ylamino)-1-hydroxyethyl)-5-hydroxybenzo[d]thiazol-2(3H)-oneacetate salt

(R)-1-(5-tert-butoxy-2-isopropoxybenzo[d]thiazol-7-yl)-2-(1-(4-butoxyphenyl)-2-methylpropan-2-ylamino)ethanol,(1 equiv.) was suspended in isopropanol. At 50 to 60°, a 1M aqueoushydrochloric acid solution (3 equiv.) was added within about 30-60 min.After complete reaction (approx. 2.5 hours at 60° C.) the solution wascooled to 20° C. and sodium hydroxide 2M (3 equiv.) added gradually atthis temperature. After complete addition the emulsified free base(R)-7-(2-(1-(4-butoxyphenyl)-2-methylpropan-2-ylamino)-1-hydroxyethyl)-5-hydroxybenzo[d]thiazol-2(3H)-onewas extracted into ethylacetate and the organic layer washed with water.The organic layer was treated with activated carbon and filtered usingmicrocrystalline cellulose as a filter aid. The filter cake was washedwith ethyl acetate. The filtrate, containing the free base(R)-7-(2-(1-(4-butoxyphenyl)-2-methylpropan-2-ylamino)-1-hydroxyethyl)-5-hydroxybenzo[d]thiazol-2(3H)-one,was carefully concentrated to a defined residual volume by distillationat a jacket temperature of 55° C. under reduced pressure.Isopropylacetate was then added and partly removed by distillation to adefined residual volume at a jacket temperature of 55° C. under reducedpressure. Further isopropylacetate and a solution of acetic acid inisopropylacetate were added to the warm distillation residue at 50-55°C. During the acetic acid addition the batch was seeded with(R)-7-(2-(1-(4-butoxyphenyl)-2-methylpropan-2-ylamino)-1-hydroxyethyl)-5-hydroxybenzo[d]thiazol-2(3H)-oneacetate salt to initiate the controlled crystallization of the acetatesalt early at 50-55° C. After gradually cooling to 0° C. the productsuspension was filtered and washed twice with cold isopropylactetate.The filter cake was dried at 50 to 90° C. under reduced pressure untilconstant weight to give crystalline(R)-7-(2-(1-(4-butoxyphenyl)-2-methylpropan-2-ylamino)-1-hydroxyethyl)-5-hydroxybenzo[d]thiazol-2(3H)-oneacetate salt at a typical yield of approx. 80%.

EXAMPLE 4(R)-7-(2-(1-(4-butoxyphenyl)-2-methylpropan-2-ylamino)-1-hydroxyethyl)-5-hydroxybenzo[d]thiazol-2(3H)-oneglycolate salt

500 mg (1.161 mmol) of free base(R)-7-(2-(1-(4-butoxyphenyl)-2-methylpropan-2-ylamino)-1-hydroxyethyl)-5-hydroxybenzo[d]thiazol-2(3H)-onewas suspended in 10.0 ml acetonitrile and 0.25 ml water in a 50 mLfour-necked flask and paddle stirred at r.t. The suspension was heatedat an internal temperature of 60° C. (jacket temperature 85° C.) and 90mg 2-hydroxyacetic acid (1.161 mmol) added to the solution. 0.25 mlwater was then added at an internal temperature of 60° C. The solutionwas seeded with(R)-7-(2-(1-(4-butoxyphenyl)-2-methylpropan-2-ylamino)-1-hydroxyethyl)-5-hydroxybenzo[d]thiazol-2(3H)-oneglycolate at an internal temperature of 30° C. and stirred overnight (16h) at r.t. Another 10 ml acetonitrile was added and stirred over theweekend at r.t. The suspension was filtered at r.t. through a glassfilter and washed once with 1.0 ml acetonitrile/water 9:1 v/v and twicewith 1.0 ml acetonitrile. 320 mg wet filter cake was dried in a dryingoven overnight (16 h) at r.t. to dryness.

Preparation of(R)-7-(2-(1-(4-butoxyphenyl)-2-methylpropan-2-ylamino)-1-hydroxyethyl)-5-hydroxybenzo[d]thiazol-2(3H)-oneglycolate seeds

63.0 mg (0.146 mmol) of free base(R)-7-(2-(1-(4-butoxyphenyl)-2-methylpropan-2-ylamino)-1-hydroxyethyl)-5-hydroxybenzo[d]thiazol-2(3H)-oneand 11.24 mg (0.146 mmol) glycolic acid were dissolved in 1.0 mlacetonitrile and 0.05 ml water. The solution was stirred at r.t. with amagnetic stirrer. Precipitation took place overnight. The suspencion wasfiltered at r.t. through a glass filter and washed three times with 0.5ml acetonitrile. The wet filter cake was dried in a drying ovenovernight (16 h) at r.t. to dryness. Yield: 52 mg white powder

EXAMPLES 5, 6 and 7

XRPD and DSC analysis of crystalline(R)-7-(2-(1-(4-butoxyphenyl)-2-methylpropan-2-ylamino)-1-hydroxyethyl)-5-hydroxybenzo[d]thiazol-2(3H)-oneand its acetate and glycolate salt forms

XRPD analysis of free base crystalline(R)-7-(2-(1-(4-butoxyphenyl)-2-methylpropan-2-ylamino)-1-hydroxyethyl)-5-hydroxybenzo[d]thiazol-2(3H)-oneand its acetate and glycolate salt forms was carried out under thefollowing experimental conditions:

XRPD method Instrument Bruker D8 Advance (reflection) Irradiation CuKα(40 kV, 30 mA) Step 0.017grd Scan type Continuous scan Scan time 107.1 sScan range 2°-40° (2 theta value)

DSC analysis was carried out under the following experimentalconditions:

DSC method Instrument Perkin Elmer Diamond Temperature range 30°-300 C.Sample mass 2-3 mg Sample pan Aluminium closed Nitrogen flow 20-50 K/min

EXAMPLE 5 XRPD analysis of crystalline(R)-7-(2-(1-(4-butoxyphenyl)-2-methylpropan-2-ylamino)-1-hydroxyethyl)-5-hydroxybenzo[d]thiazol-2(3H)-one

Free base(R)-7-(2-(1-(4-butoxyphenyl)-2-methylpropan-2-ylamino)-1-hydroxyethyl)-5-hydroxybenzo[d]thiazol-2(3H)-onewas recrystallised as described below prior to XRPD analysis.

4.0 g (2.232 mmol) of(R)-7-(2-(1-(4-butoxyphenyl)-2-methylpropan-2-ylamino)-1-hydroxyethyl)-5-hydroxybenzo[d]thiazol-2(3H)-onewas suspended in 24.0 ml ethyl acetate in a 100 ml four-necked flask andpaddle stirred at r.t. The suspension was dissolved at an internaltemperature of 70° C. (jacket temperature 90° C.) to provide a clearyellow solution. The solution was cooled down over 30 min. at r.t. andseeded with free base(R)-7-(2-(1-(4-butoxyphenyl)-2-methylpropan-2-ylamino)-1-hydroxyethyl)-5-hydroxybenzo[d]thiazol-2(3H)-oneat an internal temperature of 35° C. (crystallisation taking place veryslowly) and stirred overnight (16 h) at r.t. The solution was thenfiltered at r.t. through a glass filter (fast filtration, duration: <1min.) and washed 3× with 2.0 ml ethyl acetate (clear yellow motherliquor). 5.82 g wet filter cake was dried in a drying oven overnight 16h at r.t. and 16 h at 40° C.

Yield: 3.63 g white powder (90.75%)

The crystalline(R)-7-(2-(1-(4-butoxyphenyl)-2-methylpropan-2-ylamino)-1-hydroxyethyl)-5-hydroxybenzo[d]thiazol-2(3H)-onewas analysed by XRPD and the characteristic peaks are shown in the tablebelow (see also FIG. 5). Of these, the peaks at 8.5, 13.3, 13.9, 14.4,15.2, 17.2, 17.5, 18.1, 21.3 and 22.5° 2-theta are the mostcharacteristic.

Angle (2-Theta °) Intensity % 8.5 medium 11.4 medium 12.7 medium 13.3medium 13.9 medium 14.4 medium 15.2 medium 17.2 high 17.5 high 18.1 high21.3 medium 21.7 high 22.5 high 23.3 high 23.6 medium 24.4 medium 25.6medium 26.1 high 26.6 high 27.9 medium 28.5 medium 28.9 medium

Crystalline free base(R)-7-(2-(1-(4-butoxyphenyl)-2-methylpropan-2-ylamino)-1-hydroxyethyl)-5-hydroxybenzo[d]thiazol-2(3H)-onewas analysed by DSC and found to have an onset of melting at about 115°C.

EXAMPLE 6 XRPD analysis of crystalline(R)-7-(2-(1-(4-butoxyphenyl)-2-methylpropan-2-ylamino)-1-hydroxyethyl)-5-hydroxybenzo[d]thiazol-2(3H)-oneacetate salt

Crystalline(R)-7-(2-(1-(4-butoxyphenyl)-2-methylpropan-2-ylamino)-1-hydroxyethyl)-5-hydroxybenzo[d]thiazol-2(3H)-oneacetate salt was analysed by XRPD and the characteristic peaks are shownin the table below (see also FIG. 6). Of these, the peaks at 8.8, 11.5,16.4, 17.6, 18.2, 19.6, 20.1, 20.8, and 21.1° 2-theta are the mostcharacteristic.

Angle (2-Theta °) Intensity % 8.8 high 10.0 low 11.5 high 14.2 low 14.6low 15.7 low 16.4 high 17.6 medium 18.2 high 19.1 low 19.6 medium 20.1high 20.8 high 21.1 medium 23.3 medium 26.2 low 26.6 medium 27.1 medium

Crystalline(R)-7-(2-(1-(4-butoxyphenyl)-2-methylpropan-2-ylamino)-1-hydroxyethyl)-5-hydroxybenzo[d]thiazol-2(3H)-oneacetate salt was analysed by DSC and found to have a broad endotherm ataround 170° C.

EXAMPLE 7 XRPD analysis of crystalline(R)-7-(2-(1-(4-butoxyphenyl)-2-methylpropan-2-ylamino)-1-hydroxyethyl)-5-hydroxybenzo[d]thiazol-2(3H)-oneglycolate salt

Crystalline(R)-7-(2-(1-(4-butoxyphenyl)-2-methylpropan-2-ylamino)-1-hydroxyethyl)-5-hydroxybenzo[d]thiazol-2(3H)-oneglycolate salt was analysed by XRPD and the characteristic peaks areshown in the table below (see also FIG. 7). Of these, the peaks at 8.7,11.6, 16.1, 18.0, 19.8, 20.7, and 21.1° 2-theta are the mostcharacteristic.

Angle (2-Theta °) Intensity % 8.7 high 11.6 medium 16.1 high 17.4 medium18.0 high 19.2 medium 19.8 high 20.7 high 21.1 high 22.6 low 23.1 medium23.3 medium 23.7 low 26.2 high 26.8 medium 27.9 low 28.3 low

Crystalline(R)-7-(2-(1-(4-butoxyphenyl)-2-methylpropan-2-ylamino)-1-hydroxyethyl)-5-hydroxybenzo[d]thiazol-2(3H)-oneglycolate salt was analysed by DSC and found to have an onset of meltingat about 188° C.

EXAMPLE 8 Method for the Preparation of a Pharmaceutical FormulationSuitable for Subcutaneous Administration of Compound a in Acetate SaltForm

For 1.00 liter drug product solution approximately 900 g of water forinjection is placed into a clean vessel suitable for pharmaceuticalcompounding. 50 g mannitol, 0.60 g acetic acid and 10 g benzyl alcoholis added and dissolved in the water for injection. 1.00 g of Compound Ais then added and dissolved. pH is adjusted to the target value, forexample 5.0, with 1N sodium hydroxide solution. Water for injection isthen added to the target product solution weight of 1.016 kg. The drugproduct solution is sterile filtered through a 0.22 μm PVDF membraneinto washed, depyrogenized vials, closed with sterile rubber stoppersand crimped. The vials are terminally sterilized by autoclaving.

EXAMPLE 8a Alternative Method for the Preparation of a PharmaceuticalFormulation Suitable for the Subcutaneous Administration of Compound ain Acetate Salt Form

For 1.00 liter drug product solution approximately 900 g of water forinjection is placed into a clean vessel suitable for pharmaceuticalcompounding. 50 g mannitol and 10 g benzyl alcohol is added anddissolved in the water for injection. 1.14 g of the acetate salt ofCompound A is then added and dissolved. pH is adjusted to the targetvalue, for example 5.0, with acetic acid solution. Water for injectionis then added to the target product solution weight of 1.016 kg. Thedrug product solution is sterile filtered through a 0.22 μm PVDFmembrane into washed, depyrogenized vials, closed with sterile rubberstoppers and crimped. The vials are terminally sterilized byautoclaving.

EXAMPLE 9 Comparative Solubilities of Free Base, Acetate Salt andGlycolate Salt Forms of Compound a

The relative solubilities of the free base form and the acetate andglycolate salt forms of Compound A were analysed and the results areshow in the table below. Solutions were titrated with addition of HCl orNaOH for pH adjustment. The improved aqueous solubilities of the acetateand glycolate salt forms relative to the free base form of Compound Amake the acetate and glycolate salts of Compound A more suitable forsubcutaneous injection or infusion.

Compound A free Compound A acetate Compound A glycolate base solubilityin H₂O salt solubility in H₂O salt solubility in H₂O Conc in Conc inConc in pH mg/mL pH mg/mL pH mg/mL 6.2 0.27 5.9 1.33 5.1 13.1 7.0 0.056.0 1.11 5.3 6.39 7.3 <0.01   6.1 1.10 5.4 4.47 7.8 <0.01   6.2 0.55

EXAMPLE 10 In Vitro Cellular Profiles of Compound of the Invention(Compound A), its Enantiomer (Compound B), its Racemate (Compound A/B)and Formoterol

The compound of the invention (compound A) shows the following EC₅₀values in Test 1 as described hereinbefore.

Primary cells; cAMP response CHO cells^(#) EC₅₀ (E_(max) %) EC₅₀(E_(max) %) Human Rat Compounds β2 AR β1 AR α1A AR skMC Rat skMCcardiomyocytes Formoterol 0.7 nM  85 nM 190 nM 0.2 nM 0.9 nM 2.9 nM(99%**) (86%**) Compound 5.6 nM 560 nM >10 μM 0.7 nM 3.4 nM 5.7 nM A (R)(88%**) (32%**)  (96%*) (98%*) (71%**) Compound 950 nM  >10 μM >30 μM280 nM  n.d. n.d. B (S) (83%**) (100%*) Compound  11 nM 684 nM n.d. 0.63nM  n.d. n.d. A/B (87%**) (38%**) (100%*) Compound 2.5 nM n.d. n.d. 1.7nM n.d. n.d. A (R) (91%**)  (93%**) acetate salt skMC: differentiatedskeletal myotubes; *compared to formoterol; **compared to isoprenaline;^(#)cAMP for β1 and β2, Ca²⁺ for α1A; n.d. not determined

The compound of the invention (compound A) is a potent and selective β2AR agonist with very low intrinsic efficacy on β1 AR and no activity onα1A AR. Its enantiomer Compound B is very weak on β2 AR with an EC₅₀ of950 nM.

EXAMPLE 11 Effects of Formoterol and Compound a on Skeletal Muscle andHeart Weight In Vivo

Male Wistar Han IGS (International Genetic Standard) rats (Crl:WI(Han))at the weight of 350-400 g were purchased from Charles RiverLaboratories. Rats were acclimated to the facility for 7 days. Animalswere housed in groups of 3 animals at 25° C. with a 12:12 h light-darkcycle. They were fed a standard laboratory diet containing 18.2% proteinand 3.0% fat with an energy content of 15.8 MJ/kg (NAFAG 3890, Kliba,Basel, Switzerland). Food and water were provided ad libitum. Formoterolor Compound A was dissolved in the vehicle indicated below to achieve adose range of 0.003 to 0.03 mg/kg/day for formoterol and 0.01 to 0.1mg/kg/day for Compound A with the Alzet model 2ML4 for 28 days. Pumpswere filled with the solution and kept for several hours at 37° C. inPBS until surgical implantation. Rats were treated subcutaneously withTemgesic at a dose of 0.02 mg/kg with a volume of 1 ml/kg at least 30minutes before surgery, and then the pumps filled with the solutionindicated above were implanted subcutaneously into the back of the ratsunder anesthesia with isoflurane at a concentration of 3%. Temgesic wasadministered subcutaneously to the rats 24 h and 48 h after the surgery.Body weights were measured twice per week. Clips were removed 10 daysafter the surgery under anesthesia. Four weeks after the treatment, therats were euthanized with CO₂, and the tibialis anterior, gastrocnemiusand soleus muscles, heart and brain were dissected and weighed. Brainweight was used for normalization of organ weights. Results areexpressed as mean+/−SEM. Statistical analysis was carried out usingDunnett's multiple comparison test following one-way analysis ofvariance to compare the treatment groups to the vehicle control group.Differences were considered to be significant when the probability valuewas <0.05: *: Statistical analyses were performed by GraphPad Prismversion 5.0 (GraphPad Software, Inc., La Jolla, Calif.). Muscle weightwas normalized to the body weight at day 0 (initial body weight) andheart weight was normalized by brain weight.

Study 1: Formoterol

Dose Group Treatment (mg/kg) Route Regimen 1 Vehicle* 0 s.c. Alzet 2Formoterol 0.003 minipump 3 Formoterol 0.01 2ML4 for 4 4 Formoterol 0.03weeks *Vehicle: 20% 1:2 Cremophor:Ethanol in saline (0.9% NaCl)

Study 2: Compound A

Dose Group Treatment (mg/kg) Route Regimen 1 Vehicle* 0 s.c. Alzet 2Compound A 0.01 minipump 3 Compound A 0.03 2ML4 for 4 4 Compound A 0.1weeks *Vehicle: 20% 1:2 Cremophor:Ethanol in saline (0.9% NaCl)

FIG. 1 shows that formoterol induces both skeletal muscle hypertrophyand heart mass increase to the same extent, while Compound A inducesskeletal muscle hypertrophy with minimum impact on heart mass,indicating that Compound A exhibits a selective effect on skeletalmuscle over cardiac muscle. Compound A significantly induces skeletalmuscle hypertrophy by 11% at 0.01 mg/kg/day with steady state plasmaconcentration of ˜0.2 nM, while there were no findings on the hearthistopathology even at 0.1 mg/kg/day with steady state concentration of˜2 nM.

EXAMPLE 12 Effects of Formoterol and Compound a on the Function ofIsolated Organs (Left Atrium Contraction, Sino-Atrial Node Beating Rateand Automaticity of Whole Heart) Method

Left Atrium Contraction:

The left atrium contraction assay was performed at Ricerca Biosciences,LLC (catalog no 407500 Adrenergic beta1), using left atria from DunkinHartley Guinea pig with body weight of 600+/−80 g (Arch. Int.Pharmacodyn. 1971:191:133-141.).

Sino-Atrial Node Beating Rate:

New Zealand white female rabbits were killed by exsanguination after adeep anesthesia using a mixture of ketamine/xylazine, i.v. The heart wasquickly removed and placed in Tyrode's solution. This solution wascontinuously gassed with 95% O₂, 5% CO₂, and previously warmed toapproximately 36±0.5° C. The right atrium was separated from the rest ofthe heart. The preparations were mounted in a tissue bath and kept at37±0.5° C. for at least one hour stabilization. Action potentials (AP)were intracellularly recorded with a standard glass microelectrodefilled with 3 M KCl, connected to a high input impedance-neutralizingamplifier (VF-180 microelectrode amplifier, Bio-Logic). The AP weredisplayed on a digital oscilloscope (HM-407 oscilloscope, HAMEG),analyzed by means of high resolution data acquisition system (Notocordsoftware hem 4.2, Notocord SA, Croissy, France). After one hour ofstabilization, compounds were added to the Tyrode's solution at theincreasing concentrations, each concentration being maintained for 30minutes. There was no wash-out between two concentrations.Electrophysiological measurements were made by analyzing actionpotentials during the experimental protocol at the end of the 30 minuteperfusion period. The SA spontaneous frequency was evaluated by countingthe number of beats every 10 seconds to express the results in number ofbeats per minute (bpm). Data were expressed as mean±SEM.

Automaticity:

Automaticity was investigated in the isolated Langendorff perfusedrabbit hearts, conducted by Hondeghem Pharmaceuticals Consulting N.V.,B-8400 Oostende, Belgium. The tests were run in on hearts from albinofemale rabbits weighing about 2.5 kg and having an age of approximately3 months. The compound effects were measured in a fully automated modelusing isolated rabbit heart perfused according to the Langendorfftechnique. The spontaneously beating heart is retrogradely perfused withincreasing concentrations of the test item. One electrode is carefullyplaced on the left atrium in order to record the cycle length of thesinus node automaticity.

FIGS. 2 a and 2 b show the results obtained when comparing formoterolwith compound of the invention (compound A).

Compound A shows no effects on left atrium contraction up to 10 μM andless direct effects on the pacemaker activity, compared to Formoterol.

Formoterol Compound A Left atrium contraction EC₅₀ (n = 2) 17 nM >10 μMSino-Atrial node beating rate, maximum +45% +6.2% increase (n = 6)Automaticity, maximum increase (n = 3) +46%  +17% Values in FIGS. 2a and2b are expressed as means ± SEM; Sino-atrial node (n = 6), isolatedheart (n = 3)

EXAMPLE 13 Effects of Formoterol and Compound a on the Heart Rate InVivo

Wistar Han (W-H) IGS (International Genetic Standard) rats (Crl:WI(Han))were purchased from Charles River Laboratories. Femoral arterial andvenous catheters were chronically implanted and exteriorized through aspring tether-swivel system and housed in specialized cages. Arterialcatheter was connected to a pressure transducer to continuously measurepulse pressure, mean arterial pressure and heart rate, which was derivedfrom the blood pressure signal, via a digital data acquisition system.Compounds were administered via s.c catheter implanted through the skinbuttun. Values are expressed as means±SEM (n=3).

Compound A shows less heart rate increases compared to formoterol whenadministered with s.c. bolus, up to 0.3 mg/kg as shown in FIGS. 3 a, 3 band 3 c.

EXAMPLE 14 Effects of Formoterol and Compound A on the Heart Rate InVivo

Rhesus monkeys, 24 females with body weight around 4 to 8 kg, wererandomized into 4 groups of n=6. The animals were restrained on a chairup to 4 hours after single subcutaneous administration of compounds, andthen returned to their pens. Heart rates were measured using a SurgivetV3304 device. Values are expressed as means±SEM (n=6).

Compound A shows less heart rate increase compared to formoterol whenadministered as a s.c. bolus, up to 0.03 mg/kg as shown in FIGS. 4 a and4 b.

EXAMPLE 15 Effect of Compound a, its Enantiomer (Compound B) and itsRacemate Compound A/B) on Serotonin 5-HT_(2C) Receptor

Human recombinant hr5-HT_(2C) CHO cell membranes (Biosignal Packard,USA) and ³H-Mesulergine (NEN Life Science Products, USA, 1 nM) are usedfor measuring the binding affinity of the compounds to human 5-HT_(2C)receptor. Non-specific binding is evaluated in the presence of 1 μMMesulergine. Fifty μL each of membrane, ligand and compound in a totalvolume of 250 μL are incubated in 96-well plates for 60 min at 22° C. ina buffer containing 50 mM Tris, 0.1% ascorbic acid, 10 μM Pargyline, pH7.7. The plates are filtrated, washed 3 times in ice-cold 50 mM Tris,dred and measured in Topcount.

CHO-K1 cells coexpressing mitochondrial apoaequorin, recombinantSerotonin 5-HT_(2Cne) and the promiscuous G protein G_(α16) grown tomid-log phase in culture media without antibiotics were detached withPBS-EDTA, centrifuged and resuspended in assay buffer (DMEM/HAM's F12with HEPES, without phenol red+0.1% BSA protease free) at aconcentration of 1×10⁶ cells/ml. Cells were incubated at roomtemperature for at least 4 h with coelenterazine h. Reference agonistwas a-methyl-5-HT. For agonist testing, 50 μL of cell suspension weremixed with 50 μL of test or reference agonist in a 96-well plate. Theresulting emission of light is recorded using Hamamatsu Functional DrugScreening System 6000 (FDSS 6000) luminometer. Agonist activity of testcompound was expressed as a percentage of the activity of the referenceagonist at its EC₁₀₀ concentration.

Serotonin 5-HT_(2C) Binding CHO EC₅₀ (E_(max) %) 5-HT n.d. 0.24 nMCompound A (R)  11 μM 280 nM (83%) Compound B (S) 0.8 μM 19.7 nM (99%) Compound A/B 1.7 μM  25 nM (113%)

Compound A is 50-fold less active on 5-HT_(2C) when compared to β2ARagonist activity (5.6 nM), while its enantiomer Compound B is very weakon β2AR with EC₅₀ of 950 nM but much more potent on 5-HT_(2C) with EC₅₀of 19.7 nM, showing inversed selectivity on the target.

Compound A is also over 10-fold less active on 5-HT_(2C) when comparedto the racemate or the (S) enantiomer, suggesting that the side-effectprofile of this compound is advantageous.

1. A compound of formula (I) in free form or in pharmaceuticallyacceptable salt form which is


2. A compound according to claim 1 which is(R)-7-(2-(1-(4-butoxyphenyl)-2-methylpropan-2-ylamino)-1-hydroxyethyl)-5-hydroxybenzo[d]thiazol-2(3H)-onein free form.
 3. A compound according to claim 1 which is(R)-7-(2-(1-(4-butoxyphenyl)-2-methylpropan-2-ylamino)-1-hydroxyethyl)-5-hydroxybenzo[d]thiazol-2(3H)-onein acetate salt form.
 4. A compound according to claim 1 which is(R)-7-(2-(1-(4-butoxyphenyl)-2-methylpropan-2-ylamino)-1-hydroxyethyl)-5-hydroxybenzo[d]thiazol-2(3H)-onein glycolate salt form.
 5. A pharmaceutical composition comprising atherapeutically effective amount of a compound according to claim 1 andone or more pharmaceutically acceptable carriers.
 6. A pharmaceuticalcomposition according to claim 5 wherein one of the pharmaceuticallyacceptable carriers is benzyl alcohol.
 7. A combination comprising atherapeutically effective amount of a compound according to claim 1 andone or more therapeutically active co-agents.
 8. A process for themanufacture of a compound of formula (I) in free form or inpharmaceutically acceptable salt form which includes the steps of: a.the reaction of a compound of formula (IIa) in free form or inpharmaceutically acceptable salt form

 in which R_(a) and R_(b) are protecting groups with2-(4-butoxy-phenyl)-1,1-dimethyl-ethylamine; b. the cleavage of anyprotecting groups still present; c. the recovery of the so obtainablecompound of formula (I) in free form or in pharmaceutically acceptablesalt form.
 9. A process for the manufacture of a compound of formula (I)in free form or in pharmaceutically acceptable salt form according toclaim 8 in which compound (IIa) is obtained by the reaction of acompound of formula (IIIa) in free form or in pharmaceuticallyacceptable salt form

in which in which R_(a) and R_(b) are protecting groups and LG is aleaving group with a base and optionally a phase transfer catalyst. 10.A process for the manufacture of a compound of formula (I) in free formor in pharmaceutically acceptable salt form according to claim 9 inwhich compound (IIIa) is obtained by the stereoselective reduction of acompound of formula (IVa-2) in free form or in pharmaceuticallyacceptable salt form

in which R_(a) and R_(b) are protecting groups and LG is a leavinggroup.
 11. A process according to claim 10 wherein the LG is chloro. 12.A process according to claim 11 in which compound (IVa′-2) in free formor in pharmaceutically acceptable salt form

is obtained by the reaction of a compound of formula (Va) in free formor in pharmaceutically acceptable salt form

in which R_(a) and R_(b) are protecting groups and Hal is a halogen with2-chloro-N-methoxy-N-methyl-acetamide in the presence of a strong base.